Systems and methods for treating cancer and/or augmenting organ function

ABSTRACT

Systems, methods and devices for controlled sympathectomy procedures for neuromodulation in the treatment of subjects having neoplastic conditions are disclosed. Systems, methods, and devices for interventionally treating a cancerous tumor and cancer related pain are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 14/958,659, filed on Dec. 3, 2015, now U.S. Pat. No.10,136,944, entitled “Systems and Methods for Treating Cancer and/orAugmenting Organ Function,” which claims benefit of and priority to U.S.Provisional Application Ser. No. 62/087,629, filed on Dec. 4, 2014,entitled “Systems and Methods for Treating Cancer and/or AugmentingOrgan Function”, and is a continuation-in-part application claiming thebenefit of and priority to U.S. patent application Ser. No. 14/895,744,filed on Dec. 3, 2015, now U.S. Pat. No. 10,143,419, a national stageapplication of International Application No. PCT/US2014/060471, whichclaims benefit of and priority to U.S. Provisional Application Ser. No.61/891,242 filed on Oct. 15, 2013, and Provisional Application Ser. No.62/010,699 filed on Jun. 11, 2014, each entitled “Systems and Methodsfor Treating Cancer and/or Augmenting Organ Function”, the entirecontents of which are each incorporated by reference herein.

BACKGROUND Background

Tumor growth, spread, and eventual invasion into surrounding tissues andstructures in the body continues to be an unresolved disease state,having a profound impact on cancer patient outcomes.

Aggressive therapies are often ineffective at stemming growth of thetumors over the long term, and can often contribute to pain andsuffering of treated patients.

Perineural invasion of cancerous tumors is a hallmark of many aggressiveforms of cancer. Often, patient outcomes diminish dramatically onceperineural invasion has begun. Furthermore, pain and patient discomfortmay be associated with such perineural invasion, the direct effects ofwhich can have negative impact on patient outlook, optimism, andoutcome. Long term use of analgesic medications to counteract such paincan also have detrimental effects on patient outlook, optimism, andoutcome.

There are several approaches available for treating cancer-related pain.

Opioids are often used as full agonists at the morphine receptor (e.g.,morphine, oxycodone, hydromorphone), or partial agonist opioids (e.g.,buprenorphine). Opioids hyperpolarize nociceptive cell membranes,shorten the duration of their action potentials, and inhibit the releaseof excitatory mediators. Chronic use can lead to neuropathic pain andgenerally is accompanied by many side effects.

Anti-inflammatory drugs, non-steroidal anti-inflammatory drugs (NSAIDS)decrease inflammation by inhibiting the synthesis of peripheralprostaglandins. NSAIDS are often effective at treating cancer pain thatdoes not originate from nerve damage.

Neuropathic cancer pain is often treated with anticonvulsants,antidepressants, corticosteroids, capsaicin, opioids, and lidocainepatches.

Radiotherapy, radionuclide therapy, etc. employs ionizing radiationfocused at cancer cells. Generally, this approach causes apoptotic deathof tumor cells, and radiosensitive inflammatory cells.

Neurolytic celiac plexus block can be effective in the treatment ofcancer pain but is accompanied by several risks and complications(including paraplegia). Often the celiac plexus is blocked with a 10%phenol solution or absolute alcohol solution. Celiac block can also leadto hypotension (complication of lumbar sympathetic block complications),or paraplegia due to volume spread of solution into the spinal cord.Thus, existing procedures are fraught with complications.

Intraspinal drug administration is an approach that is used to deliverpain medication directly into the spine, termed ‘spinal analgesicchemotherapy’ and can improve the effect of opioid, NSAIDS, and otherdrug treatments through localized delivery into the spine.

Bone cancer can be particularly painful. Pain progression of bone cancerpain is usually a dull, constant pain, which gradually increases inintensity over time. As the cancer progresses, a breakthrough or severepain can emerge spontaneously or with movement or load bearing. Suchbreakthrough pain is often acute, severe, debilitating, and difficult tocontrol.

SUMMARY

According to a first aspect, there is provided a system for treating acancerous tumor and/or cancer pain coupled to a target organ, and/oraltering the neural traffic in a microenvironment coupled to the targetorgan within a body, including a catheter (i.e., a balloon catheter, aneedle catheter, a flexible catheter, etc.) or a guidewire sized anddimensioned for delivery into a lumen (i.e., an artery, vein, vessel,forma, or the like) serving the target organ and/or the tumor, thecatheter or guidewire including a distal tip configured to interfacewith the walls of an artery, vein, vessel coupled to the target organ,the distal tip configured for delivery of energy and/or a substance toone or more nerves coupled to the target organ.

According to aspects, there is provided a system for altering a functionof a target organ and/or altering the neural traffic in amicroenvironment coupled to the target organ within a body, including acatheter (i.e., a balloon catheter, a needle catheter, a flexiblecatheter, etc.) or a guidewire sized and dimensioned for delivery into alumen (i.e., an artery, vein, vessel, forma, or the like) serving thetarget organ, the catheter or guidewire including a distal tipconfigured to interface with the walls of an artery, vein, vesselcoupled to the target organ, the distal tip configured for delivery ofenergy and/or a substance to one or more nerves coupled to the targetorgan.

In aspects, the distal tip may include a balloon, a basket, a deployablehelix, a deployable microneedle, a combination thereof, or the like forinterfacing with the wall.

The energy may be thermal energy, RF (radio frequency) current, MW(microwave) current, ultrasound, MR (magnetic resonance) guided HIFU(high intensity focused ultrasound), radiation, cryotherapy,combinations thereof, or the like.

In aspects, the substance may be a medicament, a denervating agent, asympathetic nerve specific denervating agent, a parasympathetic nervespecific denervating agent, a neuroblocking agent, a highly specificneuroblocking agent (i.e., an agent specifically configured for blockingof a particular receptor, nerve family, etc.), or the like. In aspects,the denervating agent may be ethanol, phenol, botulinum toxin, or thelike. In aspects, the highly specific denervating agent may be a neuraltargeting chemical, etc.

In aspects, the catheter or guidewire may include one or more sensingelements each in accordance with the present disclosure, located withinthe vicinity of the distal tip thereof, configured to interface withand/or monitor electrophysiological activity from one or more nervescoupled to the target organ upon placement (i.e., during a surgicalprocedure, etc.). One or more sensing elements may be configured anddimensioned to monitor local physiologic data, electrophysiologicaldata, neural traffic, sympathetic neural traffic, parasympathetic neuraltraffic, afferent neural traffic, efferent neural traffic, smooth muscleresponse, or the like from the target organ and/or within the vicinityof the target organ. Such information may be advantageous fordetermining the extent of a treatment, a disease state of the organ, forpredicting the response of the organ and/or a neural circuit connectedthereto to a treatment, an ablation, a delivery of energy, or the like.

In aspects, the catheter or guidewire may be equipped with a substanceeluting element, configured to deliver a substance, a medicament, adenervating substance, a combination thereof, or the like into thetarget organ, into a perivascular site surrounding the wall of thelumen, into the adventitia of the lumen, into a microenvironment of thetumor, into the lumen, into the tissues surrounding the wall of thelumen, a combination thereof, or the like.

In aspects, the energy and/or substance may be delivered and configuredto interrupt, block, and/or augment neural traffic along one or morenerves coupled to the target organ. In aspects, the energy and/orsubstance may be provided so as to block nerve traffic to and/or fromthe organ along the lumen into which the distal tip has been inserted.

In aspects, the system may include a balloon coupled with the distaltip, the balloon coupled to a fluid source so as to be expand-ablydeployed during a procedure so as to interface with the walls of lumenupon placement of the distal tip therein. The balloon may include one ormore energy delivery elements, and/or sensing elements to interface withthe wall of the lumen, one or more of the nerves, to brace the distaltip against the wall of the lumen, to alter blood flow past the distaltip, or the like.

In aspects, the system may be configured to direct energy through theenergy delivery elements based upon the information collected by thesensing elements. The sensing elements may be sized, dimensioned,shaped, and configured to monitor and/or determine the signals relatingto regions of abnormal electrophysiological activity, determine thedirection of nerve traffic along nerves in the vicinity of the lumen,sympathetic neural activity in the vicinity of the lumen, determine thetype of nerves situated near the sensing element, determine theeffectiveness of the energy and/or substance delivery, determine theresponse of nerve traffic to a stress test performed on the body or theorgan, combinations thereof, or the like. In aspects, the system may beconfigured to direct the energy delivery into one or more regions of thelumen wall, through the lumen wall, into the adventitia, into the targetorgan, adjacent to the lumen, into a microenvironment of the tumor,combinations thereof, or the like.

The system may include a stress testing element, configured to apply alocal and/or systemic stress to the body, one or more of the sensingelements configured to monitor the response of the nerves to the stress.Such stressed response may be advantageous for assessing the type,proportion of, and/or properties of the nerves in the vicinity of thelumen wall, assess the neural response to the stress state, assess thefunctionality of the organ, or the like.

The distal tip may include a characteristic diameter of less than 1 mm(millimeter), less than 0.75 mm, less than 0.5 mm, or less than 0.3 mmso as to access the lumen near to or within a site within the targetorgan.

According to aspects, there is provided use of a system in accordancewith the present disclosure to treat pain, e.g., pain associated withperineural invasion of a cancerous tumor, pain associated with neuralreceptor damage in the vicinity of inflammation and/or a tumormicroenvironment, or the like.

According to aspects, there is provided use of a system in accordancewith the present disclosure to treat and/or slow the progression of acancerous tumor. Some non-limiting examples of such cancer that may betreated include cancer of the prostate, pancreas, breast, colon, cervix,liver, bone, and the like.

According to aspects, there is provided use of a system in accordancewith the present disclosure to slow, hinder, and/or prevent perineuralinvasion of a cancerous tumor into a surrounding nerve structure.

According to aspects, there is provided use of a system in accordancewith the present disclosure to interrupt, decrease, and/or stop neuralcommunication to a cancerous tumor and/or the microenvironmentsurrounding the tumor (i.e., to interrupt nerve traffic to/from acancerous tumor or the tissues thereby to the rest of the body).

According to aspects, there is provided use of a system in accordancewith the present disclosure to destroy nerves in the vicinity of atumor.

According to aspects, there is provided use of a system in accordancewith the present disclosure to slow or even halt tumorigenesis ofcancerous tissue.

According to aspects, there is provided use of a system in accordancewith the present disclosure to treat local inflammation (such as for thetreatment of pancreatitis, prostatitis, irritable bowel syndrome, etc.).

In aspects, the system may include a balloon coupled with the catheter,situated in the vicinity of the distal tip thereof, the balloon coupledto a fluid source so as to be expand-ably deployed during a procedure soas to interface with the walls of lumen into which the distal tip may bedeployed.

In aspects, the balloon may include one or more energy deliveryelements, and/or sensing elements each in accordance with the presentdisclosure configured to interface with tissues adjacent to the balloonduring a procedure. In aspects, the sensing elements may be configuredto monitor electrophysiological information associated with the adjacenttissues.

In aspects, the system may be configured to direct energy through theenergy delivery elements based upon the information collected by thesensing elements. In aspects, the sensing elements may be used todetermine regions of abnormal electrophysiological activity, determinethe direction of nerve traffic along the lumen, determine the type ofnerves situated near the sensing element, etc. In aspects, the energydelivery may be directed to one or more regions of the lumen wall,through the lumen wall, into the adventitia surrounding a lumen, into anorgan (i.e., a pancreas, a liver, an intestinal wall, a cervix, abreast, a kidney, a bone, etc.) adjacent to the lumen, etc. as directedby data collected by the sensing elements during the procedure.

In aspects, relating to a treatment for bone cancer, the energy and/orchemical substance may be directed to one or more regions of aperiosteal space surrounding a bone and/or into a foramen at a site ofvessel entry into the bone, to neural tissues surrounding one or moreartery or vein segments near to the bone surface, within the margin ofthe bone, along the artery or vein heading to the bone, but after breakaway from a larger, less specific vessel, near the foramen of the bone,and/or periosteal space of the bone.

In aspects, the energy delivery elements and/or sensing elements may besized and arranged such that they may be placed within an artery, vein,and/or foramen of a bone. In aspects, the delivery elements and/orsensing elements may be sized and dimensioned such that a characteristicdiameter thereof is less than 1 mm, less than 0.75 mm, less than 0.5 mm,less than 0.3 mm, or the like.

In aspects, the system may include a stress testing component, thestress testing component configured to apply a stress (i.e., localand/or systemic) to the body while monitoring the response to the stressvia one or more of the sensing elements. In aspects, the stress testingcomponent may be configured to deliver one or more substances into theorgan, and/or artery coupled thereto. The substances may be selected soas to alter the functional state of the organ upon delivery thereto, thesensing elements configured to monitor a change in theelectrophysiological activity in response to the change in functionalstate. In aspects, the system may be used to diagnose a disease state,determine a function of the adjacent tissues, and/or determine the typeof adjacent tissues (i.e., a nerve fiber, a type of nerve fiber, etc.)based upon the data obtained by the one or more sensing elements duringthe stress.

In aspects, there is provided a method for treating a cancerous tumor,altering an organ function, and/or altering neural traffic in amicroenvironment coupled to the tumor or a target organ within a bodyaccessing a wall of a lumen in the vicinity of the target organ or thetumor, and delivering energy and/or a substance to at least a portion ofthe wall of the lumen, to a nerve coupled with the tumor and/or organ,through at least a portion of the wall of the lumen, and/or into thetissues surrounding the tumor and/or the organ.

In aspects, the method may include collecting physiologic data,electrophysiological data, neural traffic, sympathetic neural traffic,parasympathetic neural traffic, afferent neural traffic, efferent neuraltraffic, smooth muscle response, or the like from the target organand/or within the vicinity of the target organ. Such information may beadvantageous for determining the extent of a treatment, a disease stateof the organ, for predicting the response of the organ and/or a neuralcircuit connected thereto to a treatment, an ablation, a delivery ofenergy, or the like.

In aspects, the method may include directing the energy and/or substancebased upon the collected physiologic data.

In aspects, the method may include collecting further physiologic dataafter the delivery of energy to determine if the treatment wassuccessful.

The method may include collecting further physiologic data after thedelivery of the energy and/or the substance to determine if the deliveryaffected the microenvironment around the tumor, the nerve coupled to thetumor, and/or the perivasculature of the lumen.

The method may include applying a stress test to the subject during thecollecting of physiologic data. Some non-limiting examples of a stresstest include a valsalva maneuver, a tilt table test, elevating one ormore legs, transient sitting to standing exercises, executing a changein posture, moving from a prone position to a sitting or standingposition, a breath holding technique, or combinations thereof.

In aspects, the stress test may include injecting a vasodilator, avasoconstrictor, a neuroblocker, a neurostimulant, a diuretic, insulin,glucose, a beta-adrenergic receptor antagonist, an angiotensin-11converting enzyme inhibitor, a calcium channel blocker, an HMG-CoA(3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor, digoxin, ananticoagulant, a diuretic, a beta blocker, an ACE(angiotensin-converting enzyme) inhibitor, a steroid, or combinationthereof to the organ and/or subject and monitoring the local responsethereto. In aspects, the injection may be directed into the lumen, intothe tumor, into the adventitia surrounding the lumen, and/or into anorgan coupled thereto.

In aspects, one or more steps of a method in accordance with the presentdisclosure may be performed by a system in accordance with the presentdisclosure.

In aspects, the target organ may be a bone. The method may be used totreat bone pain, bone cancer pain, osteoporosis, etc. In aspects, theenergy and/or substance delivery may be performed in a vessel, aperiosteal space, a foramen, a medullary cavity, a combination thereof,or the like of the bone. A non-limiting example of the bone may be along bone (e.g., a femur), and the lumen may be a nutrient, epiphyseal,or metaphyseal artery, vein or forma.

In aspects, the substance may include an antibody drug conjugate (ADC),a chemotherapeutic agent, etc. In aspects, the ADC substance may beconfigured to affect the function of a region or tissue type within thevicinity of the organ alternatively to the other tissues within thevicinity thereof. In aspects, the substance may include a sugar attachedto a therapeutic agent to mask the therapeutic agent, such that it is tobe taken up by the region of tissue (i.e., appear as a sugar, a friendlyprotein, etc.). Such a configuration provides a method for delivering ahighly potent medicament directly to a tissue of interest (i.e.,directly into a tumor), so as to enhance the bioavailability thereof,and to minimize the systemic dosage required in order to achievesignificant therapeutic concentrations thereof within the region oftissue.

In aspects, the substance may be delivered at a rate of less than 1mg/hr (milligrams/hour), less than 0.01 mg/hr, less than 1 μg/hr(micrograms/hour), or the like. Such a configuration may be important soas to minimize local stress and damage caused by the introduction of thesubstance into the microenvironment of the tissue of interest.

In aspects, a system in accordance with the present disclosure mayinclude a catheter and/or a guidewire configured for percutaneous accessto the arteries, veins, or lumens, of a body, for delivery through oneor more arteries of the body to the vicinity of the target organ. Anassociated method in accordance with the present disclosure may includeinserting a tip of the catheter and/or guidewire into the artery or veinto access the neural structures near to or within the target organ.

Aspects of the invention include treatment of subjects suffering fromneoplastic disease conditions, i.e., disease conditions characterized bythe occurrence of unwanted cellular proliferation, e.g., as manifestedby the appearance/growth of one or more solid tumors. By treatment ismeant at least an amelioration of the symptoms associated with thedisease condition afflicting the subject (i.e., host), whereamelioration is used in a broad sense to refer to at least a reductionin the magnitude of a parameter, e.g., symptom, associated with thepathological condition being treated, such as size of tumor, rate ofgrowth of tumor, spread of tumor, pain, etc. As such, treatment alsoincludes situations where the pathological condition, or at leastsymptoms associated therewith, are completely inhibited, e.g., preventedfrom happening, or stopped, e.g., terminated, such that the host nolonger suffers from the pathological condition, or at least the symptomsthat characterize the pathological condition. Where the symptom beingtreated is pain, treatment in accordance with methods of the inventionresults in some instances in a decrease in the National Initiative onPain Control (NIPC) numerical scale of 1 point or more, such as 2 pointsor more, 3 points or more, 4 points or more, 5 points or more, 6 pointsor more, 7 points or more, 8 points or more, including 9 points or more.As such, treatment includes both curing and managing a pain condition.Where the symptom being treated is tumor growth, treatment in accordancewith methods of the invention results in some instances in a decrease inthe rate of tumor growth, e.g., as compared to a suitable control, wherethe magnitude of the decrease in rate may be 5% or greater, such as 10%or greater, including 20% or greater. In some instances, treatment inaccordance with methods of the invention results in a reduction in tumorsize, where the reduction may be 5% or more, including 10% or more, suchas 15% or more, e.g., 25% or more, 50% or more, 75% or more, v/v.

A variety of subjects are treatable according to the methods of theinvention. Subjects treatable as described herein include “mammals” or“mammalian,” where these terms are used broadly to describe organismswhich are within the class mammalia, including the orders carnivore(e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), andprimates (e.g., humans, chimpanzees, and monkeys). In some embodiments,the subject is human.

Aspects of the invention include treatment of subjects suffering from atumor. Examples of tumors including carcinomas, adenocarcinomas,lympohomas, sarcomas, and other solid tumors, as described in U.S. Pat.No. 5,945,403, solid tumors; benign tumors, for example hemangiomas,acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas. Insome cases, methods and compositions described herein are employed forthe treatment of subjects having, e.g., carcinomas, gliomas,mesotheliomas, melanomas, lymphomas, leukemias, adenocarcinomas, breastcancer, ovarian cancer, cervical cancer, glioblastoma, leukemia,lymphoma, prostate cancer, and Burkitt's lymphoma, head and neck cancer,colon cancer, colorectal cancer, non-small cell lung cancer, small celllung cancer, cancer of the esophagus, stomach cancer, pancreatic cancer,hepatobiliary cancer, cancer of the gallbladder, cancer of the smallintestine, rectal cancer, kidney cancer, bladder cancer, prostatecancer, penile cancer, urethral cancer, testicular cancer, cervicalcancer, vaginal cancer, uterine cancer, ovarian cancer, thyroid cancer,parathyroid cancer, adrenal cancer, pancreatic endocrine cancer,carcinoid cancer, bone cancer, skin cancer, retinoblastomas, Hodgkin'slymphoma, non-Hodgkin's lymphoma (see, CANCER: PRINCIPLES AND PRACTICE(DeVita, V. T. et al. eds 1997) for additional cancers), etc.

Where the methods are directed to treatment of subjects having one ormore solid tumors, aspects of such embodiments may include methods wheretumor tissue itself is not modulated as described herein. Instead, onlynerve(s) operatively coupled to the tumor is modulated, e.g., ablated.As such, in these embodiments the tumor itself is not ablated. Such maybe done following an assessment of which nerve(s) are suitable formodulation to achieve the desired treatment goal, e.g., using evaluationprotocols as described herein.

According to aspects, there is provided a method for treating a tumorincluding neuromodulating electrophysiological activity of one or morenerves coupled to the tumor and/or a perineural microenvironmentsurrounding the tumor. The neuromodulation may include stimulating,stressing, and/or ablating the nerves in accordance with the presentdisclosure.

In aspects, the method may include stimulating the neural circuit with astimulation frequency suitable to provide a neural block there along.

In aspects, the method may include providing energy and/or a bolus of achemical agent in an amount sufficient to provide a neural block to oneor more regions of the neural circuit, and/or ablate one or more regionsof the neural circuit.

The method may include decoupling a neurological connection between thetumor and a neural circuit in the body and/or a brain in the body,monitoring the electrophysiological activity before, during, and/orafter the step of neuromodulating, determining the effectiveness of thestep of neuromodulating based upon the monitoring, and/or determiningthe type and/or location for the step of neuromodulating based upon themonitoring.

According to aspects, there is provided use of a system and/or method inaccordance with the present disclosure to treat pancreatic cancer,prostate cancer, breast cancer, colon cancer, liver cancer, cervicalcancer, ovarian cancer, bladder cancer, bone cancer, combinationsthereof, and the like.

According to aspects, there is provided use of a system or method inaccordance with the present disclosure for preventing or slowing thegrowth rate and/or tumorigenesis of a tumor, modulating neuralcommunication between a tumor and one or more neural circuits coupled tothe target organ, augmenting/treating/ablating the perineuralmicroenvironment in the vicinity of a tumor or along a neural circuitcoupled thereto, and/or preventing or slowing the process of perineuralinvasion of a tumor into surrounding tissues

According to aspects, there is provided use of a system or method inaccordance with the present disclosure to treat osteoporosis, augmentbone density, adjust the rate of bone remodeling, alter the formation ofosteoblasts, or the like.

In aspects, a method in accordance with the present disclosure mayinclude inserting the distal tip of a device in accordance with thepresent disclosure into a vessel coupled to the tumor. In aspects, themethod may include advancing the tip of the device along the vessel suchthat the tip may interact with a wall of the vessel sufficiently near tothe tumor so as to selectively interact with the neural structurescoupled specifically to the tumor. Such positioning may be advantageousso as to minimally influence other neural structures in the body whileinteracting with those coupled to the tumor. In one non-limiting examplerelated to the treatment and/or pain reduction of a bone cancer tumorlocated in the diaphysis region of a femur, the method may includeadvancing the tip of the device along an artery or vein within the bodyso as to reach the nutrient artery and/or vein near to the femur (i.e.,sufficiently near such that the nerves running alongside the arteryand/or vein are primarily coupled with the femur as opposed to nearbymuscles, skin, peroneal nerves, or the like). In aspects, the tip may beadvanced along the nutrient artery so as to enter a branch dedicated tothe femur, so as to interact with the vessels near to the periosteum ofthe femur, near to the foramen where the nutrient artery or vein entersthe femur, to pass within the medullary cavity of the femur, or thelike. In aspects a method to treat a tumor and/or pain associatedtherewith in the epiphysis and/or metaphysis of a femur may includeaccessing an epiphyseal and/or metaphyseal artery with a tip of a devicein accordance with the present disclosure.

In aspects, a method in accordance with the present disclosure mayinclude applying energy and/or a chemical agent into an adventitia ofthe vessel.

In aspects, a method in accordance with the present disclosure mayinclude monitoring electrophysiological activity along a wall of thevessel. The method may include monitoring neural activity, nervetraffic, sympathetic neural activity, parasympathetic neural activity,afferent neural traffic, efferent neural traffic, differentiatingbetween one or more of the types of traffic, monitoring traffic during astress test, before and/or after stimulation and/or treatment of thetissues, or the like.

In aspects, the method may include using the monitoring to determine theextent of a treatment, to alter a bolus of energy or chemical agentdelivered, or the like. In aspects, such determination may be made bymonitoring one or more changes in the electrophysiological signals,changes in the neural traffic, changes in a proportion of afferentand/or efferent traffic in the vicinity of the vessel wall, changes inthe response of traffic to a stress test, to a stimulation, or the like.

According to aspects, there is provided a method for treating a tumorincluding inducing apoptosis within neural tissues within the vicinityof the tumor, within a neural circuit coupled with the tumor, or thelike. Such treatment may be provided by a system and/or method inaccordance with the present disclosure.

According to aspects, there is provided a method for treating a tumorincluding inducing necrosis within neural tissues within a neuralcircuit coupled with the tumor.

In aspects, the method may include ablating one or more nerves coupledto the tumor, while substantially limiting damage to the tissuessurrounding the nerves, substantially limiting damage to an organcoupled to the tumor, substantially limiting local inflammation, or thelike.

In aspects, induced necrosis will typically cause the correspondingcells to exhibit rapid swelling, lose membrane integrity, shut downmetabolism, and release their contents into the environment. Cells thatundergo rapid necrosis in vitro do not often have sufficient time orenergy to activate apoptotic machinery and thus will often not expressapoptotic markers. Rather, induced apoptosis typically causes thecorresponding cells to exhibit cytological and molecular events such asa change in the refractive index of the cell, cytoplasmic shrinkage,nuclear condensation, and cleavage of DNA into regularly sizedfragments.

In aspects, the chemical agent may be selected so as to induce apoptosisin one or more neural tissues (i.e., axon, dendrite, cell body, myelinsheath, synapse, etc.).

According to aspects, there is provided use of one or more systems,methods, and devices each in accordance with the present disclosure forinterventionally altering one or more homeostatic processes within abody.

Some non-limiting examples of homeostatic processes includeproduction/release of renin, insulin, cholesterol, bile salts,testosterone, progesterone, prion, serotonin, endorphins, dopamine,monoamine neurotransmitters, histamines, noradrenaline, glucose, and thelike, adjustment of blood pressure, anti-inflammatory activity,testosterone, estrogen, “uterine hemorrhaging”, hunger, bowel movement,nutritional uptake in the bowel, bone density, a rate of boneremodeling, formation of osteoblasts and the like.

In aspects, a system in accordance with the present disclosure mayinclude a substance delivery aspect, configured for elution of asubstance into the vicinity of the target.

In aspects, the system may include one or more sensing elementsconfigured for monitoring of one or more physiologic parametersassociated with the target, the homeostatic process in question, astress response, or the like.

In aspects, the system may include one or more energy delivery elementsconfigured to deliver a bolus of energy to the target in order to alterthe homeostatic process.

Aspects of the invention further include combining the disclosedneuromodulatory protocols with one or more neoplastic diseasetherapeutic and/or palliative therapies. For example, the presentdevices and methods may be used in combination with the use of one ormore anti-cancer agents. As used herein, anti-cancer agents (usedinterchangeably with “anti-tumor or anti-neoplastic” agent) include anyanti-cancer therapies, such as radiation therapy, surgery, hyperthermiaor hyperthermia therapy, or anti-cancer compounds useful in thetreatment of cancer. These include any agents, when used alone or incombination with another agent, that can alleviate, reduce, ameliorate,prevent, or place or maintain in a state of remission of clinicalsymptoms or diagnostic markers associated with neoplastic disease,tumors and cancer, and can be used in methods, combinations andcompositions provided herein. Exemplary anti-cancer compounds include,but are not limited to, cytokines, chemokines, growth factors,photosensitizing agents, toxins, anti-cancer antibiotics,chemotherapeutic compounds, radionuclides, angiogenesis inhibitors,signaling modulators, anti-metabolites, anti-cancer vaccines,anti-cancer oligopeptides, mitosis inhibitor proteins, antimitoticoligopeptides, anti-cancer antibodies (e.g., single-chain antibodies),anti-cancer antibiotics, immunotherapeutic agents, bacteria and anycombinations thereof. Exemplary cytokines and growth factors include,but are not limited to, interleukins, such as, for example,interleukin-1, interleukin-2, interleukin-6 and interleukin-12, tumornecrosis factors, such as tumor necrosis factor alpha (TNF-α),interferons such as interferon gamma (IFN-γ) granulocyte macrophagecolony stimulating factors (GM-CSF), angiogenins, and tissue factors.Photosensitizing agents include, but are not limited to, for example,indocyanine green, toluidine blue, aminolevulinic acid, texaphyrins,benzoporphyrins, phenothiazines, phthalocyanines, porphyrins such assodium porfimer, chlorins such as tetra(m-hydroxyphenyl)chlorin ortin(IV) chlorin e6, purpurins such as tin ethyl etiopurpurin,purpurinimides, bacteriochlorins, pheophorbides, pyropheophorbides orcationic dyes. Radionuclides, which depending upon the radionuclide,amount and application can be used for diagnosis and/or for treatment.They include, but are not limited to, for example, a compound ormolecule containing 11 Carbon, 11 Fluorine, 13 Carbon, 15 Nitrogen, 18Fluorine, 19 Fluorine, 32 Phosphate, 60 Cobalt, 90 Yttirum, 99Technetium, 103 Palladium, 106 Ruthenium, 111 Indium, 117 Lutetium, 125Iodine, 131 Iodine, 137 Cesium, 153 Samarium, 186 Rhenium, 188 Rhenium,192 Iridium, 198 Gold, 211 Astatine, 212 Bismuth or 213 Bismuth. Toxinsinclude, but are not limited to, chemotherapeutic compounds such as, butnot limited to, 5-fluorouridine, calicheamicin, maytansine, double-chainricin, ricin A chain, abrin, abrin A chain, saporin, modeccin, modeccinA chain, Pseudomonas aeruginosa exotoxin, Cholera toxin, Shigella toxin,E. coli heat labile toxin and Diptheria toxin, doxorubicin, daunomycin,methotrexate, taxol, ricin A, colchicine, cytochasins, monensin,ouabain, mitoxanthrone, vindesine, vinblastine, vincristine andenterotoxin. Anti-metabolites include, but are not limited to,methotrexate, 5-fluorouracil, 6-mercaptopurine, cytosine arabinoside,hydroxyurea and 20-chlorodeoxyadenosine. Signaling modulators include,but are not limited to, for example, inhibitors of macrophage inhibitoryfactor, toll-like receptor agonists and stat 3 inhibitors. Anti-cancerantibiotics include, but are not limited to, anthracyclines such asdoxorubicin hydrochloride (adriamycin), idarubicin hydrochloride,daunorubicin hydrochloride, aclarubicin Hydrochloride, epirubicinhydrochloride and purarubicin hydrochloride, enomycin, phenomycin,pleomycins such as pleomycin and peplomycin sulfate, mitomycins such asmitomycin C, actinomycins such as actinomycin D, zinostatinstimalamerand polypeptides such as neocarzinostatin. Anti-cancer antibodiesinclude, but are not limited to, Rituximab (RITUXAN), ADEPT, Trastuzumab(HERCEPTIN), Tositumomab (BEXXAR), Cetuximab (ERBITUX), Ibritumomab (90Y-Ibritumomab tiuexetan; ZEVALIN), Alemtuzumab (Campath-1H), Epratuzumab(Lymphocide), Gemtuzumab ozogamicin (MYLOTARG), Bevacimab (AVASTIN), andEdrecolomab (PANOREX). Angiogenesis inhibitors include, but are notlimited to, collagenase inhibitors such as metalloproteinases andtetracyclines such as minocycline, naturally occurring peptides such asendostatin and angiostatin, fungal and bacterial derivatives, such asfumagillin derivatives like TNP-470, aptamer antagonist of VEGF,batimastat, Captopril, cartilage derived inhibitor (CDI), genistein,interleukin 12, Lavendustin A, medroxyprogesterone acetate, recombinanthuman platelet factor 4 (rPF4), taxol, D-gluco-D-galactan sulfate(Tecogalan(=SP-PG, DS-4152)), thalidomide, thrombospondin.Chemotherapeutic compounds include, but are not limited to platinum;platinum analogs (e.g., platinum coordination complexes) such ascisplatin, carboplatin, oxaliplatin, DWA2114R, NK121, IS 3 295, and254-S; anthracenediones; vinblastine; alkylating agents such as thiotepaand cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfanand piposulfan; aziridines such as benzodopa, carboquone, meturedopa anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamime nitrogen mustardssuch as chiorambucil, chlornaphazine, cholophosphamide, estramustine,ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride,melphalan, novembichin, phenesterine, prednimustine, trofosfamide,uracil mustard; nitrosureas such as carmustine, chlorozotocin,fotemustine, lomustine, nimustine, ranimustine; antibiotics such asaclacinomysins, actinomycin, authramycin, azaserine, bleomycins,cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin,chromomycins, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin,olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfornithine; elliptinium acetate; etoglucid; galliumnitrate; substituted ureas; hydroxyurea; lentinan; lonidamine;mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet;pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine;anti-cancer polysaccharides; polysaccharide-K; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol;

pipobroman; gacytosine; cytosine arabinoside; cyclophosphamide;thiotepa; taxoids, such as paclitaxel and doxetaxel; chlorambucil;gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; etoposide(VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine;vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin;XELODA; ibandronate; CPT11; topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO); retinoic acid; esperamicins;capecitabine; methylhydrazine derivatives; Erlotinib (TARCEVA);sunitinib malate (SUTENT); and pharmaceutically acceptable salts, acidsor derivatives of any of the above. Also included in this definition areanti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens including, for example, tamoxifen,raloxifene, aromatase inhibiting 4 (5)-imidazoles, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone and toremifene (FARESTON);adrenocortical suppressants; and antiandrogens such as flutamide,nilutamide, bicalutamide, leuprolide and goserelin; and pharmaceuticallyacceptable salts, acids or derivatives of any of the above. Suchchemotherapeutic compounds that can be used herein include compoundswhose toxicities preclude use of the compound in general systemicchemotherapeutic methods. As used herein, an anti-cancer oligopeptide oran anti-tumor oligopeptide is short polypeptide that has the ability toslow or inhibit tumor growth and/or metastasis. Anti-cancer oligopeptidetypically have high affinity for and specificity to tumors enabling themto target tumors. Such oligopeptides include receptor-interactingcompounds, inhibitors of protein-protein interactions, enzymeinhibitors, and nucleic acid-interacting compounds. As used herein anantimitotic oligopeptide is an oligopeptide that inhibits cell division.An antimitotic oligopeptide is an exemplary anti-cancer oligopeptide.Exemplary antimitotic oligopeptides include, but are not limited to,tubulysin, phomopsin, hemiasterlin, taltobulin (HTI-286, 3), andcryptophycin.

According to aspects, there is provided a method for blocking at leastone of one or more nerves and one or more lymphatic ducts coupled to atleast one of a tumor and a metastatic cell within a body. In aspects,the blocking step isolates at least one of the tumor and the metastaticcell within the body. In aspects, the blocking step alters growth ratesof at least one of the tumor and metastatic cell within the body. Inaspects, the blocking step is performed by injecting a neurolytic agentinto at least one of the nerves, the lymphatic ducts and nearby tissue.In aspects, the blocking step includes injecting a mild inflammatoryagent into at least one of the nerves and the lymphatic ducts. Inaspects, at least one of the one or more nerves and at least one of theone or more lymphatic ducts being blocked is at least 10 mm, 20 mm, or25 mm in length.

In aspects, the method may include accessing at least one of the nervesand the lymphatic ducts via one of a nearby artery, a vein and a duct.

In aspects, the method provides that the blocking step further comprisesaltering the structure of a perineural sheath of one or more nerves. Inaspects, the blocking step further comprises performing architecturaldestruction of at least one of nerve tissue and lymphatic ductal tissuevia inflammation. In aspects, the blocking step further comprisesforming scar tissue along at least one of the nerves and the lymphaticducts.

In aspects, the method provides that the blocking step further comprisesusing a single therapeutic compound. In aspects, the compound comprisesone of an ablative agent, a migration limiting agent, and aninflammatory accelerating agent. In aspects, the blocking step treats atleast one of a tumor, a metastasis migration and cancer pain.

In aspects, the method may include confirming completion of the blockingstep. In aspects, confirmation is performed at least in part by at leastone of a system, a device, and a sensor positioned within at least oneof a nearby tissue site, an artery, a vein, and a duct.

In aspects, the method includes sensing neural traffic along the nervesat least one of before, during, and after the blocking step to at leastone of locate the nerves and confirm completion of the block.

In aspects, the method provides that the blocking step, the confirmationstep and the sensing step may be performed at least in part by a devicein accordance with the present disclosure. In aspects, the device mayinclude a balloon, a basket, a deployable helix, a deployablemicroneedle, or a combination thereof inserted into at least one of anearby artery, a vein, and a duct arranged so as to interface with thenerves upon deployment.

According to aspects, a method is provided for blocking at least one ofone or more nerves and one or more lymphatic ducts traveling along alumen coupling a first organ to at least a second organ in a body. Inaspects, the blocking step prevents metastasis of a tumor from the firstorgan to the second organ in the body. In aspects, the first organ is apancreas and the second organ is one of a spleen, a stomach, a gallbladder, a liver and a duodenum.

In aspects, the method provides that the blocking step further comprisesapplying energy to at least one of the nerves and lymphatic ducts. Inaspects, the energy is thermal energy, radio frequency current,microwave current, ultrasound, radiation, cryotherapy, or a combinationthereof.

In aspects, the method provides that the blocking step is performed atleast in part by a substance. In aspects, the substance is a medicament,a denervating agent, a sympathetic nerve specific denervating agent, aparasympathetic nerve specific denervating agent, a neuroblocking agent,a highly specific neuroblocking agent, or a combination thereof.

According to aspects, a method is provided for treating neurogenicpathways associated with cancer progression.

BRIEF DESCRIPTION OF THE DRAWINGS

Several aspects of the disclosure can be better understood withreference to the following drawings. In the drawings, like referencenumerals designate corresponding parts throughout the several views.

FIG. 1 shows aspects of a device in accordance with the presentdisclosure inserted into a lumen within a body coupled with a targetorgan.

FIG. 2 shows a schematic of aspects of a system in accordance with thepresent disclosure.

FIGS. 3a-3c show aspects of access and treatment regions for a targetorgan in accordance with the present disclosure.

FIG. 4 shows aspects of access and treatment regions for a target organin accordance with the present disclosure.

FIG. 5 shows aspects of access and treatment regions for a target organin accordance with the present disclosure.

FIG. 6 shows aspects of access and treatment regions for a target organin accordance with the present disclosure.

FIGS. 7a-7c show aspects of methods for treating and/or assessingfunction of a neural structure in accordance with the presentdisclosure.

FIGS. 8a and 8b show aspects of access and treatment regions for atarget organ in accordance with the present disclosure.

FIGS. 9a-9d show aspects of a device in accordance with the presentdisclosure.

FIGS. 10a-10n show aspects of distal tips associated with a device(e.g., guidewire, catheter, micro-tool, etc.) in accordance with thepresent disclosure.

FIG. 11a shows exemplary IVIS images taken with the same settingsillustrating median tumor bioluminescence at 3 weeks post procedure inthe control group (left) and the EtOH group (right) in accordance withthe present disclosure.

FIG. 11b shows exemplary logarithms of the IVIS measured bioluminescencelevels at 3 weeks post procedure corresponding to the control group(triangles) and the EtOH group (circles) in accordance with the presentdisclosure.

FIG. 11c shows a graph illustrating the mass difference between controlgroup and EtOH group at 7 weeks in accordance with the presentdisclosure.

DETAILED DESCRIPTION

Particular embodiments of the present disclosure are described hereinwith reference to the accompanying drawings; however, the disclosedembodiments are merely examples of the disclosure and may be embodied invarious forms. Therefore, specific structural and functional detailsdisclosed herein are not to be interpreted as limiting, but merely as abasis for the claims and as a representative basis for teaching oneskilled in the art to variously employ the present disclosure invirtually any appropriately detailed structure. Like reference numeralsmay refer to similar or identical elements throughout the description ofthe figures.

Before the methods of the present disclosure are described in greaterdetail, it is to be understood that the methods are not limited toparticular embodiments described, as such may, of course, vary. It isalso to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the methods. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the methods, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the methods.

Certain ranges are presented herein with numerical values being precededby the term “about.” The term “about” is used herein to provide literalsupport for the exact number that it precedes, as well as a number thatis near to or approximately the number that the term precedes.

In determining whether a number is near to or approximately aspecifically recited number, the near or approximating unrecited numbermay be a number which, in the context in which it is presented, providesthe substantial equivalent of the specifically recited number.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the methods belong. Although any methods similar orequivalent to those described herein can also be used in the practice ortesting of the methods, representative illustrative methods andmaterials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present methods are not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

It is appreciated that certain features of the methods, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the methods, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable sub-combination. All combinations of the embodiments arespecifically embraced by the present invention and are disclosed hereinjust as if each and every combination was individually and explicitlydisclosed, to the extent that such combinations embrace operableprocesses and/or devices/systems/kits. In addition, all sub-combinationslisted in the embodiments describing such variables are alsospecifically embraced by the present methods and are disclosed hereinjust as if each and every such sub-combination was individually andexplicitly disclosed herein.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentmethods. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

According to a first aspect there is provided a controlled nerveablation/neuromodulation system, which is configured for use in methodsas described herein and may include the capability to sense one or morephysiologic parameters at one or more points in the vicinity of asurgical site or within an affected/target organ, as well as include thecapability to stimulate, deliver a chemical agent to, deliver energy to,and/or ablate tissues at one or more of the same points and/or analternative point in the vicinity of a surgical site. The nerve ablationsystem may be configured so as to access vessels and/or surgical sitesin the body. The non-limiting examples disclosed herein may be directedtowards such configurations (e.g., to controllably provideneuromodulation procedures to an organ within a body, so as tocontrollably ablate renal nerves along a renal artery via an endoscopicor percutaneous procedure, to treat a cancerous tumor, to limitperineural invasion of cancerous cells into a nearby nerve, to alter atumor microenvironment, etc.).

In aspects, a system/surgical tool in accordance with the presentdisclosure may be used to access, monitor, and/or to treat one or moreneurological pathways, ganglia, and/or sensory receptors within a body:Ampullae of Lorenzini (respond to electric field, salinity, temperature,etc.), baroreceptors, chemoreceptors, hydroreceptors, mechanoreceptors,nociceptors, osmoreceptors (osmolarity sensing), photoreceptors,proprioceptors, thermoreceptors, combinations thereof, and the like.Such receptors may be associated with one or more organs and/orphysiologic processes within the body (i.e., a regulatory process,etc.).

In aspects, a surgical tool in accordance with the present disclosuremay take the form of a guidewire. The guidewire may be dimensioned andconfigured for placement within a lumen of a body at and/or beyond asurgical site and/or anatomical site of interest, so as to monitor oneor more physiologic signals near the tip thereof. In aspects, theguidewire may provide a pathway for delivery of a second surgical deviceto the surgical site.

In aspects, a guidewire in accordance with the present disclosure mayinclude one or more energy delivery means for delivering energy to ananatomical site within and/or beyond the wall of a lumen into which theguidewire tip has been placed.

In aspects, a guidewire in accordance with the present disclosure mayinclude one or more sensors (e.g., as located on a micro-tool-tip, aclamp, a hook, a wire element, an electrode in a matrix, etc.) near tothe tip thereof. One or more sensors may include a pressure sensor, atonal sensor, a temperature sensor, an electrode (e.g., sized, oriented,and configured to interact with a local tissue site, provide a stimulusthereto, measure a potential therefrom, monitor current to/from thetissues, to measure, dependent on configuration and design, abioimpedance, measure an evoked potential, an electromyographic signal[EMG], an electrocardiographic signal [ECG], an extracellular potentialform a nearby neural structure, a mechanomyographic signal [MMG], localneural traffic, local sympathetic nerve traffic, local parasympatheticnerve traffic, afferent nerve traffic, efferent nerve traffic, etc.), anacoustic sensor, an oxygen saturation sensor, or the like.

In aspects, such sensing may be used in combination with a stress test,before/during/after an ablation, stimulation, administration of achemical, or the like to assess the effect of the procedure on theneural traffic, tissue viability, or the like. Additional detailsrelating to the sensing can be found in U.S. patent application Ser. No.14/374,466, entitled “Controlled Sympathectomy and Micro-AblationSystems and Methods,” which is incorporated by reference herein.

In aspects, a guidewire in accordance with the present disclosure mayinclude one or more analyte sensors, configured to measure one or moreanalyte concentrations or concentration trend before, during, and/orafter a procedure within a body. Such analyte sensors may be provided inan electrochemical form, a fluorescent form, an electro-optical form, aswelling responsive gel, etc.

A sensing guidewire in accordance with the present disclosure may beadvantageous for accessing very small anatomical sites within a body,accessing adjunct arteries and/or arteriole pathways along a bloodsupply to a target organ, accessing a plurality of vessels coupled to anorgan, accessing the parenchyma of an organ, for highly localizedinteraction with a tissue site, for accessing otherwise challenginglumens (i.e., a lumen with substantially small diameter, withsubstantially tortuous shape, etc.). In aspects, a guidewire inaccordance with the present disclosure may provide a means for directingone or more additional tools to a surgical site within a body. Inaspects, a guidewire in accordance with the present disclosure may beconfigured to sense physiologic parameters from and/or to treat tissueswithin such miniature lumens as part of a procedure (i.e., a surgicalprocedure, a diagnostic procedure, an ablation procedure, etc.). Such aconfiguration may be particularly advantageous for accessing a vesselwithin a small organ or microvascular region of an organ, such as with abone, near to a foramen of a bone, or the like.

In aspects, a system for treating a cancerous tumor coupled to a targetorgan within a body in accordance with the present disclosure mayinclude a catheter (i.e., a balloon catheter, a needle catheter, aflexible catheter, etc.), or a guidewire, sized and dimensioned fordelivery into a lumen (i.e., an artery, vein, vessel, or the like)serving the target organ, the catheter or guidewire including a distaltip configured to interface with the walls of an artery, vein, vesselcoupled to the target organ, the distal tip configured for delivery ofenergy and/or a substance to one or more nerves coupled to the targetorgan.

In aspects, a system for augmenting function of a target organ within abody in accordance with the present disclosure may include a catheter(i.e., a balloon catheter, a needle catheter, a flexible catheter, etc.)or a guidewire, sized and dimensioned for delivery into a lumen (i.e.,an artery, vein, vessel, or the like) serving the target organ, thecatheter or guidewire including a distal tip configured to interfacewith the walls of an artery, vein, vessel coupled to the target organ,the distal tip configured for delivery of energy and/or a substance toone or more nerves coupled to the target organ. In aspects, the energymay be thermal energy, RF current, MW current, ultrasound, radiation,cryotherapy, or the like.

In aspects, the substance may be a neurolytic agent, a mild inflammatoryagent, a medicament, a denervating agent, a sympathetic nerve specificdenervating agent, a parasympathetic nerve specific denervating agent, aneuroblocking agent, a highly specific neuroblocking agent (i.e., anagent specifically configured for blocking of a particular receptor,nerve family, etc.), or the like. In aspects, the denervating agent maybe ethanol, botulinum toxin, or the like. In aspects, the highlyspecific denervating agent may be a neural targeting chemical such as apoison, a toxin, or the like. In aspects, the neurolytic agent may beethanol. In aspects, the mild inflammatory agent may be ethanol,poly(lactic-ω-glycolic acid) (PLGA), polysaccharides, collagen, silicaparticles, carbon micro or nanoparticles, microbeads, etc.

In aspects, the catheter or guidewire may include one or more sensingelements each in accordance with the present disclosure, located withinthe vicinity of the distal tip thereof, configured to interface andrecord physiologic information associated with one or more nervescoupled to the target organ upon placement (i.e., during a surgical orinterventional procedure, during a diagnostic procedure, a stress test,etc.). In aspects, the catheter or guidewire may be equipped with asubstance eluting element, configured to deliver a substance, amedicament, a denervating substance, or the like into the target organ,into the tissues surrounding the wall of the lumen, etc. In aspects, theenergy and/or substance is delivered to interrupt and/or augment neuraltraffic along one or more nerves coupled to the target organ. Inaspects, the energy and/or substance is provided so as to block nervetraffic to and/or from the organ along the lumen into which the distaltip has been inserted. In aspects, a system a system in accordance withthe present disclosure may be used to treat pain, pain associated withperineural invasion of a cancerous tumor, or the like.

Some non-limiting examples of systems, devices, and methods which may besuitable for performing one or more aspects of a surgery, interventionalprocedure, diagnostic, and/or treatment in accordance with the presentdisclosure are generally detailed in co-pending international patentapplications including International Publication Nos. WO 2014/070999, WO2013/181137, WO 2013/112844, WO 2013/042847, WO 2013/067726, and WO2014/031962, the disclosures of which are expressly incorporated hereinby reference.

In aspects, a system, device, and/or method in accordance with thepresent disclosure may be used to treat and/or slow the progression of acancerous tumor. Some non-limiting examples of such cancer that may betreated include cancer of the prostate, pancreas, breast, colon, skin,liver, esophagus, cervix, bone, urogenitals, lung, and the like.

In aspects, a system, device, and/or method in accordance with thepresent disclosure may be used to slow, hinder, and/or preventperineural invasion of a cancerous tumor into a surrounding nervestructure. In aspects, a system, device, and/or method in accordancewith the present disclosure may be used to interrupt, decrease, and/orstop neural communication to a cancerous tumor and/or themicroenvironment surrounding the tumor (i.e., to interrupt nerve trafficto/from a cancerous tumor or the tissues thereby to the rest of thebody). In aspects, a system, device, and/or method in accordance withthe present disclosure may be used to decrease pain signals communicatedby nerves in the vicinity of the organ and/or tumor to one or moreneural circuits, ganglia, etc. In aspects, a system, device, and/ormethod in accordance with the present disclosure may be used to block,deaden, and/or to destroy nerves in the vicinity of a tumor and/orsurrounding tissues.

In aspects, a system, device, and/or method in accordance with thepresent disclosure may be used to slow or even halt tumorigenesis ofcancerous tissue.

In aspects, a system, device, and/or method in accordance with thepresent disclosure may be configured to form a physical barrier (i.e.,lesion, a collagen block, etc.). In aspects, a system, device, and/ormethod in accordance with the present disclosure may be used to treatlocal inflammation (such as for the treatment of pancreatitis,prostatitis, irritable bowel syndrome, etc.).

In aspects, the system may include a balloon coupled with the catheter,situated in the vicinity of the distal tip thereof, the balloon coupledto a fluid source so as to be expand-ably deployed during a procedure soas to interface with the walls of lumen into which the distal tip hasbeen placed. In aspects, the balloon may include one or more energydelivery elements, and/or sensing elements each in accordance with thepresent disclosure configured to interface with tissues adjacent to theballoon during a procedure. In aspects, the sensing elements may beconfigured to monitor electrophysiological information associated withthe adjacent tissues.

In aspects, the system may be configured to direct energy through theenergy delivery elements based upon the information collected by thesensing elements. In aspects, the sensing elements may be used todetermine regions of abnormal electrophysiological activity, determinethe direction of nerve traffic along the lumen, determine the type ofnerves situated near the sensing element, etc. In aspects, the energydelivery may be directed to one or more regions of the lumen wall,through the lumen wall, into the adventitia in the vicinity of thelumen, into an organ (i.e., a pancreas, a liver, an intestinal wall, akidney, a bone, etc.) adjacent to the lumen, etc. as directed by datacollected by the sensing elements during the procedure.

In aspects, the system may include a stress testing aspect, configuredto apply a stress (i.e., local and/or systemic) to the body whilemonitoring the response to the stress via one or more of the sensingelements. In aspects, the system may be used to diagnose a diseasestate, determine a function of the adjacent tissues, and/or determinethe type of adjacent tissues (i.e., a nerve fiber, a type of nervefiber, etc.) based upon the data obtained by the one or more sensingelements during the stress.

In aspects, a method in accordance with the present disclosure fortreating a cancerous tumor, may include inserting at least a portion ofa system in accordance with the present disclosure into a lumen with awall in the vicinity of a target organ, and delivering energy and/or asubstance to at least a portion of the wall of the lumen, through atleast a portion of the wall of the lumen, into the target organ, and/orinto the tissues surrounding the target organ. The method may includetreating one or more nerves in the vicinity of the target organ.

In aspects, the method may include collecting physiologic data from thetarget organ and/or within the vicinity of the target organ, collectingdata from one or more neural structures coupled to the organ, or thelike. The method may include making a diagnostic decision, determiningthe state of the local neural structures, determining the extent of asurgical procedure, etc. based at least in part from the recorded data.In aspects, the method may include directing the energy and/or substancebased upon the collected physiologic data. In aspects, the method mayinclude collecting further physiologic data after the delivery of energyto determine if the desired effect has been achieved. In aspects, themethod may include comparing a neural activity associated with theprocedure, treatment, and/or target organ before and after a procedure,to determine the extent of the procedure, to confirm that the procedurepositively affected the functionality of the nerves, etc.

In aspects, the substance may include an antibody drug conjugate (ADC),a chemotherapeutic agent, a toxin, a neurotoxin, etc. In aspects, theADC substance may be configured to affect the function of a region ortissue type within the vicinity of the organ alternatively to the othertissues within the vicinity thereof. In aspects, the substance mayinclude a sugar attached to a therapeutic agent to mask the therapeuticagent, such that it is to be taken up by the region of tissue (i.e.,appear as a sugar, a friendly protein, etc.). Such a configurationprovides a method for delivering a highly potent medicament directly toa tissue of interest (i.e., directly into a tumor), so as to enhance thebioavailability thereof, and to minimize the systemic dosage required inorder to achieve significant therapeutic concentrations thereof withinthe region of tissue.

In aspects, the substance may be delivered at a rate of less than 1mg/sec (milligrams/second), 1 mg/min (milligrams/minute), 1 mg/hr, 0.01mg/hr, 1 μg/hr, or the like. Such a configuration may be important so asto minimize local stress and damage caused by the introduction of thesubstance into the microenvironment of the tissue of interest.

In aspects, a system in accordance with the present disclosure mayinclude a catheter and/or a guidewire configured for percutaneous accessto the arteries, veins, or lumens, of a body, for delivery through oneor more arteries of the body to the vicinity of the target organ.

In aspects, one or more energy delivery elements, sensing elements, adiameter of the catheter, guidewire, or the like may be sized andarranged such that it may be placed within an artery, vein in a regionnear the target organ, within the parenchyma of the target organ, into avessel in the periosteal space of a bone, and/or through a foramen of abone. In aspects, the delivery elements and/or sensing elements,catheter, guidewire, etc. may be sized and dimensioned such that acharacteristic diameter thereof is less than 1 mm, less than 0.75 mm,less than 0.5 mm, less than 0.3 mm, or the like.

According to aspects, there is provided a method for treating a tumorincluding stimulating, blocking, and/or ablating one or more regions ofa neural circuit coupled to the tumor and/or perineural microenvironmentsurrounding a tumor. In aspects, the method may include performing thetreatment without substantially increasing inflammation, necrotizingtissues, or the like in the vicinity of the tumor.

In aspects, the method may include stimulating the neural circuit with astimulation frequency suitable to provide a neural block there along. Inaspects, the method may include providing energy and/or a bolus of achemical agent in an amount sufficient to provide a neural block to oneor more regions of the neural circuit, and/or ablate one or more regionsof the neural circuit.

In aspects, a system, device, and/or method in accordance with thepresent disclosure may be used to prevent or slow the growth rate and/ortumorigenesis of a cancerous tissue, modulating neural communicationbetween a tumor and one or more neural circuits coupled to the targetorgan, augmenting/treating/ablating the perineural microenvironment inthe vicinity of a tumor or along a neural circuit coupled thereto,and/or preventing or slowing the process of perineural invasion of atumor into surrounding tissues

In aspects, a method in accordance with the present disclosure fortreating a tumor within a body may include neuromodulating one or morenerves coupled to the tumor. In aspects, a method in accordance with thepresent disclosure for treating a tumor within a body may includeneuromodulating a perineural microenvironment in the vicinity of thetumor. In aspects, a method in accordance with the present disclosurefor treating a tumor within a body coupled with a neural circuit withinthe body may include decoupling the neurological connection between thetumor and the neural circuit. In aspects, a method in accordance withthe present disclosure may be used to treat prostate cancer, pancreaticcancer, breast cancer, colon cancer, cervical cancer, ovarian cancer,bladder cancer, or the like.

In aspects, a method in accordance with the present disclosure mayinclude inserting the distal tip of a device in accordance with thepresent disclosure into a vessel coupled to the tumor. In aspects, themethod may include placing the distal tip of a device into a vessel,such as an artery, which supplies blood to the tumor, and/or uniquelysupplies blood to the organ coupled with the tumor.

In aspects, a method in accordance with the present disclosure mayinclude applying energy and/or a chemical agent into an adventitiasurrounding the vessel. In aspects, a method in accordance with thepresent disclosure may include monitoring electrophysiological activityalong a wall of the vessel. In aspects, the method may include using themonitoring to determine the extent of a treatment, to alter a bolus ofenergy or chemical agent delivered, or the like.

In aspects, a method in accordance with the present disclosure fortreating a tumor may include inducing apoptosis within neural tissueswithin the vicinity of the tumor, within a neural circuit coupled withthe tumor, or the like.

In aspects, a method in accordance with the present disclosure mayinclude inducing necrosis, and/or apoptosis within neural tissues withina neural circuit coupled with the tumor. In aspects, induced necrosiswill typically cause the corresponding cells to exhibit rapid swelling,lose membrane integrity, shut down metabolism, and release theircontents into the environment. Cells that undergo rapid necrosis invitro do not often have sufficient time or energy to activate apoptoticmachinery and thus will often not express apoptotic markers. Rather,induced apoptosis typically causes the corresponding cells to exhibitcytological and molecular events such as a change in the refractiveindex of the cell, cytoplasmic shrinkage, nuclear condensation, andcleavage of DNA into regularly sized fragments. In aspects, the chemicalagent may be selected so as to induce apoptosis in one or more neuraltissues (i.e., axon, dendrite, cell body, myelin sheath, synapse, etc.).

In aspects, one or more systems, methods, and devices each in accordancewith the present disclosure may be used to interventionally alter one ormore homeostatic processes within a body. Some non-limiting examples ofhomeostatic processes include production/release of renin, insulin,cholesterol, bile salts, testosterone, progesterone, prion, serotonin,endorphins, dopamine, monoamine neurotransmitters, histamines,noradrenaline, glucose, and the like, adjustment of blood pressure,anti-inflammatory activity, testosterone, estrogen, “uterinehemorrhaging”, hunger, bowel movement, nutritional uptake in the bowel,and the like.

In aspects, a system in accordance with the present disclosure mayinclude a substance delivery aspect, configured for elution of asubstance into the vicinity of the target. In aspects, the system mayinclude one or more sensing elements configured for monitoring of one ormore physiologic parameters associated with the target, the homeostaticprocess in question, a stress response, or the like. In aspects, thesystem may include one or more energy delivery elements configured todeliver a bolus of energy to the target in order to alter thehomeostatic process.

According to aspects, there is provided a method for blocking at leastone of one or more nerves and one or more lymphatic ducts coupled to atleast one of a tumor and a metastatic cell within a body. In aspects,the blocking step isolates at least one of the tumor and the metastaticcell within the body. In aspects, the blocking step alters growth ratesof at least one of the tumor and metastatic cell within the body. Inaspects, the blocking step is performed by injecting a neurolytic agentinto at least one of the nerves, the lymphatic ducts and nearby tissue.In aspects, the blocking step includes injecting a mild inflammatoryagent into at least one of the nerves and the lymphatic ducts. Inaspects, at least one of the one or more nerves and at least one of theone or more lymphatic ducts being blocked is at least 10 mm, 20 mm, or25 mm in length.

In aspects, injection of the mild inflammatory agent may be performedthrough the wall of the artery to minimize collateral damage to thesurrounding tissues. In aspects, microneedles, either with or withoutsensing capability, may be inserted through the wall of the vessel. Inaspects, the mild inflammatory agent may be delivered into theadventitia around the vessel, where the nerves are situated. In aspects,neural traffic may be sensed with sensing enabled microneedles (or othermeans if the microneedles do not have sensing capability). In aspects,the method includes determining whether the microneedles are close tothe nerves, releasing the mild inflammatory agent when the microneedlesare close to the nerves, monitoring the nerves (e.g., via changes intraffic), and pulling out the microneedles to finish the procedure.

In aspects, blocking may refer to the blocking of neural traffic along anerve (such as via disrupting the function of the nerve at one or moresites thereupon, over stimulating the nerve so as to functionally blocktraffic thereupon, changing the electrical potentials around the nerve,altering the ionic concentrations in and/or around the nerve, and/ordestroying one or more functional features of the nerve at one or moresites thereupon). In aspects, blocking may refer to physically blockingthe channel taken up by the nerve (i.e. the physical space taken up bythe nerves, which form channels through an associated tissue volume).Such physical blocking may be useful to limit axonal regrowth of thenerve after the procedure, to disrupt channel pathways, which mayfacilitate cell migration, or the like. For example, inflammation may beinduced to close off the channels and limit or hinder nerve regrowthafter the procedure.

In aspects, the method may include accessing at least one of the nervesand the lymphatic ducts via one of a nearby artery, a vein and a duct.

In aspects, the method provides that the blocking step further comprisesaltering the structure of a perineural sheath of one or more nerves. Inaspects, the blocking step further comprises performing architecturaldestruction of at least one of nerve tissue and lymphatic ductal tissuevia inflammation. In aspects, the blocking step further comprisesforming scar tissue along at least one of the nerves and the lymphaticducts.

In aspects, architectural destruction of at least one of nerve tissueand lymphatic ductal tissue may be effected by a mild inflammatoryagent. In aspects, architectural destruction of at least one of nervetissue and lymphatic ductal tissue may be effected by a dedicatedingredient in a substance, such as, but not limited to, silica and PLGAbeads.

In aspects, the method provides that the blocking step further comprisesusing a single therapeutic compound. In aspects, the compound comprisesone of an ablative agent, a migration limiting agent, and aninflammatory accelerating agent. In aspects, the blocking step treats atleast one of a tumor, a metastasis migration and cancer pain.

In aspects, the method may include confirming completion of the blockingstep. In aspects, confirmation is performed at least in part by at leastone of a system, a device, and a sensor positioned within at least oneof a nearby tissue site, an artery, a vein, and a duct.

In aspects, the method includes sensing neural traffic along the nervesat least one of before, during, and after the blocking step to at leastone of locate the nerves and confirm completion of the block.

According to aspects, a method is provided for blocking at least one ofone or more nerves and one or more lymphatic ducts traveling along alumen coupling a first organ to at least a second organ in a body. Inaspects, the blocking step prevents metastasis of a tumor from the firstorgan to the second organ in the body. In aspects, the first organ is apancreas and the second organ is one of a spleen, a stomach, a gallbladder, a liver and a duodenum.

In aspects, the method provides that the blocking step further comprisesapplying energy to at least one of the nerves and lymphatic ducts. Inaspects, the energy is thermal energy, radio frequency current,microwave current, ultrasound, radiation, cryotherapy, or a combinationthereof.

In aspects, the method provides that the blocking step is performed atleast in part by a substance. In aspects, the substance is a medicament,a denervating agent, a sympathetic nerve specific denervating agent, aparasympathetic nerve specific denervating agent, a neuroblocking agent,a highly specific neuroblocking agent, or a combination thereof.

According to aspects, a method is provided for treating neurogenicpathways associated with cancer progression.

FIG. 1 shows aspects of a device in accordance with the presentdisclosure inserted into a lumen within a body coupled with a targetorgan. A micro surgical tool 1610 in accordance with the presentdisclosure is shown as placed into the renal artery 2 of a subject ascoupled to a target organ 1 (i.e., here shown as a kidney) in accordancewith the present disclosure. In aspects, the microsurgical tool 1610 mayinclude one or more distal tips 1620 each including one or more sensingtips in accordance with the present disclosure to selectively sense,stimulate, and/or treat target anatomy based on the determined locationsthereof. In aspects, the sensing tips may be configured to acquirepositional and/or physiologic information related to the target anatomy,placement of the micro surgical tool 1610 within the renal artery 2, theparenchyma of the target organ 1, and/or monitoring of the surgicalprocedure (i.e., ablation procedure, chemical denervation, chemicaldeployment, etc.), or the like. Such a feedback mechanism may be used toprecisely guide the micro surgical tool 1610 during a surgical procedure(i.e., ablation procedure, etc.), to determine the extent of a surgicalprocedure, or the like. In aspects, the distal tip 1620 may be coupledwith a controller 1630 in accordance with the present disclosure forperforming one or more of the procedures.

FIG. 2 shows a schematic of aspects of a system for performing asurgical procedure in accordance with the present disclosure. The systemis shown interfacing with a surgical site 2101 within a body, a subject,a patient, etc. The system may include a microsurgical tool 2110 inaccordance with the present disclosure. During use, the microsurgicaltool 2110 may be configured to interact 2112 with the surgical site 2101in accordance with the present disclosure. In aspects, the microsurgicaltool 2110 may be coupled to a connector 2120, the connector providing amechanical and/or electrical interface between the microsurgical tool2110 and/or one or more other modules of the system. In aspects, themicrosurgical tool 2110 may include an embedded local control circuit2115 a (e.g., a microcircuit, a switch network, a signal conditioningcircuit, etc.) in accordance with the present disclosure. In aspects,the connector 2120 may include a local control circuit 2115 b inaccordance with the present disclosure. In aspects, the connector 2120may be coupled to an operator input device 2125 (i.e., a foot pedal, anadvancing slider, a torqueing mechanism, a recording button, an ablationbutton, etc.). In aspects, the connector 2120 may be coupled to acontrol unit 2130 configured to accept one or more signals from themicrosurgical tool 2110, communicate one or more control signalsthereto, send one or more pulsatile and/or radio frequency signals tothe microcontroller, record one or more electrophysiological signalsfrom the microsurgical tool, or the like.

In aspects, the control unit 2130 may be connected to a display 2135configured to present one or more aspects of the recorded signals fromthe microsurgical tool 2110 to an operator, to present a map, at leastpartially dependent on the recorded signals, to present one or moremetrics relating to a physiologic parameter, a surgical procedure,surgical outcome efficacy, etc. In aspects, the control unit 2130 may becoupled to a surgical subsystem 2140, the surgical subsystem 2140configured to perform a surgical procedure 2145 to the surgical site2101. Some non-limiting examples of suitable surgical procedures includean ablation, an excision, stimulation, a cut, a burn, a radio frequencyablation, radiosurgery, an ultrasonic ablation, an abrasion, a biopsy,and delivery of a substance. The control unit 2130 may be configured toinfluence, direct, control, and/or provide feedback for one or moreaspects of the surgical procedure 2145, based upon one or more of theelectrophysiological signals conveyed by the microsurgical tool 2110.

FIGS. 3a-3c show aspects of access and treatment regions for a targetorgan in accordance with the present disclosure. Each of FIGS. 3a-3cshow a pancreas 2201 (i.e., a target organ in accordance with thepresent disclosure), a spleen 2203 (i.e., optionally a target organ inaccordance with the present disclosure), and a duodenum 2205. FIG. 3aillustrates aspects of a vascular supply to the pancreas 2201, spleen2203, and duodenum 2205, including the aorta 2207, the celiac trunk2209, the anterior superior pancreaticoduodenal artery 2211, theposterior superior pancreaticoduodenal artery 2213, the anteriorinferior pancreaticoduodenal artery 2215, the posterior inferiorpancreaticoduodenal artery 2217, the superior mesenteric artery 2219,the dorsal pancreatic artery 2221, and the splenic artery 2223. As partof a treatment, monitoring session, etc. in accordance with the presentdisclosure, one or more microsurgical tools each in accordance with thepresent disclosure may be inserted into and/or interfaced with one ormore of the vascular supply vessels to the pancreas 2201, spleen 2203,and/or duodenum 2205. In aspects, one or more of the microsurgical tooltips may be delivered through the aorta 2207, the celiac trunk 2209,and/or the superior mesenteric artery 2219, or branches thereof, etc. Inaspects, one or more microsurgical tools in accordance with the presentdisclosure may be configured to treat the perivasculature in thevicinity of one or more of the vascular supply lumens in accordance withthe present disclosure.

In aspects, a pancreatic tumor may be present within or coupled with thepancreas 2201. In such aspects, a microsurgical tool in accordance withthe present disclosure may be interfaced with one or more of thevascular supply lumens in order to treat the pancreatic tumor inaccordance with the present disclosure.

In aspects, the treatment may be applied to one or more neurologicalstructure in the vicinity of the vascular supply. In aspects, aprocedure (i.e., a treatment, biopsy, sensing, stimulation, etc.) may beapplied to a first zone 2227 located in the vicinity of the posteriorand/or anterior superior pancreaticoduodenal arteries 2211, 2213. Inaspects, such a zone may be located along the posterior and/or anteriorpancreaticoduodenal arteries 2211, 2213 distally to the hepatic artery2225. In aspects, a procedure in accordance with the present disclosuremay be performed on a second zone 2229 located in the vicinity of theanterior and/or posterior inferior pancreaticoduodenal arteries 2215,2217 in accordance with the present disclosure. In aspects, the secondzone 2229 may include tissues in the vicinity and/or wall of thesuperior mesenteric artery 2219. In aspects, a procedure in accordancewith the present disclosure may be performed on a third zone 2231,located in the vicinity of the dorsal pancreatic artery 2221 ortributaries formed therefrom. In aspects, a procedure in accordance withthe present disclosure may be performed on a fourth zone 2233, locatedin the vicinity of the splenic artery 2223 or tributaries formedtherefrom. In aspects, one or more zones 2227, 2231, 2233 may includeregions of the celiac trunk 2209. In aspects, a surgical procedure maybe applied simultaneously within one or more zones 2227, 2229, 2231,2233, and/or vascular supply lumens, etc. In aspects, one or more distaltips of one or more surgical tools may be inserted into a zone 2227,2229, 2231, 2233 as part of a procedure in accordance with the presentdisclosure.

In aspects, a plurality of distal tips may be simultaneously locatedwithin one or more zones. Energy provided via one or more of the distaltips may be communicated between zones 2227, 2229, 2231, 2233, and/or toan externally coupled component (i.e., an electrode). In aspects, thedistal tips may be configured to perform a first procedure (i.e., asensing procedure) within a first zone 2227, 2229, 2231, 2233 and toperform a second procedure (i.e., a stimulation, ablation, chemicaldelivery, etc.) within a second zone 2227, 2229, 2231, 2233, or thelike.

In aspects, such procedures may be performed to augment and/orplastically change neural communication to/from one or more regions of atarget organ 2201 to the brain, a ganglion, etc. so as to influence thephysiologic function thereof, to augment the afferent traffic to thebrain, to augment the efferent traffic reaching the target organ, etc.

In aspects, a procedure may be applied to the celiac trunk 2209, thethird zone 2231, and/or the fourth zone 2233 in order to affect functionof the spleen 2203.

In aspects, coordination of two or more procedures applied within one ormore zones 2227, 2229, 2231, 2233 may be provided to treat one or moreregions of the target organ 2201 (i.e., in this case so as toselectively treat one or more regions of the pancreas 2201 whilemaintaining regular function of one or more other regions of thepancreas 2201, etc.). In aspects, the zones 2227, 2229, 2231, 2233 to betreated may be selected based upon an image of the target organ 2201(i.e., to determine the location and coupling of an anomaly, a tumor,etc. within the target organ 2201). In aspects, a first procedure, suchas sensing and/or stimulation, applied within one or more of the zones2227, 2229, 2231, 2233 may be provided to determine where within thetarget organ to provide a second procedure (i.e., sensing, ablation,etc.), or to determine the extent of a previously applied procedure(i.e., an ablation procedure, a neuromodulation procedure, etc.).

In aspects, the zones and/or anatomical features shown in FIG. 3a may beaccessed through the aorta 2207, such as from a descending approach 2235or an ascending approach 2237 as preferred by a surgeon or surgicalplanner.

FIG. 3b shows aspects of a pancreas 2201, a spleen 2203, and a duodenum2205 along with the vascular supply thereto. Aspects of the vascularsupply shown include the portal vein 2241, the posterior superiorpancreaticoduodenal vein 2243, the anterior superior pancreaticoduodenalvein 2245, the splenic vein 2247, the anterior inferiorpancreaticoduodenal vein 2249, and the posterior inferiorpancreaticoduodenal vein 2251. Aspects of the tributaries that serve thevascular supply are shown as line segments interconnecting the largervessels with the pancreas 2201, the spleen 2203, and the duodenum 2205.

In aspects, one or more zones 2255, 2257, 2259 may be accessed as partof a procedure and monitored, stimulated, treated, etc. in accordancewith the present disclosure. In aspects as part of a method inaccordance with the present disclosure, one or more of the zones 2255,2257, 2259 may be accessed via a portal vein approach 2253 (i.e., via acatheter, guidewire, surgical tool, etc. placed into the portal vein).In aspects, one or more zones 2255, 2257, 2259 may be accessed viadirect needle stick into the body as part of a procedure.

In aspects, one or more treatments may be applied to one or more of thezones 2255, 2257, 2259 as part of a procedure. Such treatments may beprovided so as to affect the perineural microenvironment surrounding atumor within the target organ, to affect one or more receptors, sensorynerves, or the like within the target organ, to affect one or morephysiologic functions of the organ, etc.

FIG. 3c illustrates a pancreas 2201, spleen 2203, and a duodenum 2205,and a pancreatic duct 2265 running through the length of the pancreas2201. The pancreatic duct 2265 supplies pancreatic fluids into theduodenum via the duodenal papilla 2267. In aspects, a system and/ormethod in accordance with the present disclosure may be used to treatone or more zones 2275, 2277 within the vicinity of the pancreatic duct2265. In aspects, a surgical tool in accordance with the presentdisclosure may be introduced 2273 into the pancreatic duct 2265 via theduodenal papilla 2267, from a descending approach 2271 through theesophagus, stomach, and duodenum 2205.

In aspects, one or more of the zones 2275, 2277 may be monitored, and/ortreated in accordance with the present disclosure. In aspects, suchtreatment may be used to affect secretion of pancreatic fluid into theduodenum 2205, affect cell function within the vicinity of thepancreatic duct 2265, affect the microenvironment of a tumor locatedwithin the pancreas 2201, to disconnect one or more neural pathwaysbetween a tumor and another neural circuit within the body, etc. Inaspects, one or more of the treatments may be provided as part of asurgical procedure coupled with a pancreas resection, as part of asurgical intervention to treat pancreatic cancer, etc. In aspects, oneor more treatments (i.e., stimulations, ablations, chemical agentdelivery, neural blocks, etc.) may be configured to influence one ormore functions of the target organ. In the case of the pancreas 2201,the treatments may be employed to affect one or more functions such asproduction of insulin, glucagon, somatostatin, and/or pancreaticpolypeptide, production/secretion of pancreatic juice containingdigestive enzymes, glucose metabolism, and/or control of blood glucoseconcentration.

Generally speaking, the part of the pancreas with endocrine function ismade up of approximately a million cell clusters called islets ofLangerhans. Four main cell types exist in the islets: a cells secreteglucagon (increase glucose in blood), β cells secrete insulin (decreaseglucose in blood), delta cells secrete somatostatin (regulates/stops aand β cells) and PP cells, or gamma cells, secrete pancreaticpolypeptide.

Secretion of hormones into the blood may be affected and/or regulated bythe effect of hormones in the blood on the islets of Langerhans, andthrough the effect of the autonomic nervous system on the blood flow andcell function. In aspects, augmentation of sympathetic and/orparasympathic activity may affect secretion from beta cells, and alphacells within the pancreas.

FIG. 4 shows aspects of access and treatment regions for a target organin accordance with the present disclosure. A schematic diagram of aliver 2301, along with coupled vasculature including an aorta 2303, ahepatic vein 2305, hepatic arteries 2307, a portal vein 2309, and ductsincluding hepatic ducts 2313. A gallbladder 2315 is also shown, and mayserve as a target organ for a procedure in accordance with the presentdisclosure. A plurality of zones 2333, 2335, 2337, 2339 may be accessedvia the vasculature and/or ducts, and may be monitored and/or treated aspart of a procedure in accordance with the present disclosure. Inaspects, different neural circuits (sympathetic, parasympathetic, and/orafferent circuits), may travel through the various zones 2333, 2335,2337, 2339. A monitoring procedure, optionally combined with a stresstest, may be used to elucidate the type and/or function of neuralcircuits within the vicinity of one or more zones 2333, 2335, 2337,2339, within a sub-region of a zone 2333, 2335, 2337, 2339, or the like.

In aspects, one or more neural circuits coupled with the liver 2301 maybe selectively treated in accordance with the present disclosure. Inaspects, one or more neural circuits passing along a hepatic duct 2313may be monitored and/or treated in accordance with the presentdisclosure. In aspects, a hepatic duct 2313 situated zone 2337, or azone 2335, 2339 situated in the vicinity of the hepatic arteries 2307may be accessed through a hepatic duct 2313 approach 2329, and/or via anascending approach 2323 through the aorta 2303, a descending approach2321 through the aorta 2303, an ascending approach 2345 through theportal vein 2309, an ascending approach 2325 through the inferior venacava 2311, and potentially a descending approach 2319 through theinferior vena cava 2311.

In aspects, one or more procedures in accordance with the presentdisclosure may be applied to the liver 2301, the parenchyma of the liver2301, hepatocytes of the liver 2301, to disruption and/or augmentationof signals that can be relayed electrically to individual cells bystructures such as cell-to-cell connecting gap junctions, to gapjunctions within cells of the parenchyma (i.e., via modulation ofelectrotonic coupling, to compensate for the sparse direct inputs to thehepatocytes, especially with respect to sympathetic signaltransduction), one or more zones 2333, 2335, 2337, 2339, within regionsof receptors within the liver 2301 so as to modulate hormone releaseinto the organ, one or more vessels and/or perivascular regions coupledwith the liver 2301, and/or the gallbladder 2315 to treat a diseasestate, to augment organ function, or the like.

Some aspects of liver function that may be augmented by a treatmentand/or monitored in accordance with the present disclosure includeglucose storage/release, metabolic sensing (and related signal trafficto the brain related thereto), glucoregulatory function, afferent vagalactivity reaching the brain, chemoreceptor function (or related signaltraffic associated therewith), lipid sensing/synthesis, regulation ofhepatic insulin sensitizing substance, afferent traffic augmentationassociated with glucosensors (i.e., primarily in the region of theportal vein 2309, etc.), protein sensing, GLP-1, leptin, CCK, FFA, PPARalpha and gamma, glycogenolysis, gluconeogenesis, VLDL secretion,ketogenesis, hypoglucemia sensing, or the like.

In aspects, one or more procedures (i.e., sensing, a treatment,stimulation, ablation, etc.) may be applied to one or more vagalbranches including the hepatic branch, the gastroduodenal branch, thecommon hepatic branch, coupled with the left vagal and right vagal nervebranches. In aspects, such procedures may be performed along theassociated vasculature serving the liver 2301 and/or within theparenchyma of the liver 2301 in the vicinity of the corresponding neuralstructures of the vagal branch in question. In aspects, monitoring ofthe vagal branch at a first location (i.e., along an artery supplyingthe liver 2301) and at a second location (i.e., at a site within theparenchyma of the liver 2301) may be used to confirm proper placement ofa surgical tool at a treatment site, confirm efficacy of a treatment,confirm proper targeting of the associated neural structures related tothe vagal branch, etc.

In aspects, one or more sympathetic procedures in accordance with thepresent disclosure may be applied to one or more sympathetic and/orafferent nerves in the vicinity of the liver 2301, the gallbladder 2315,along a vessel or duct serving the organs, etc.

In aspects, one or more surgical tools in accordance with the presentdisclosure may be used to provide a physical and/or functional mappingof one or more neural circuits within one or more regions of the liverneuronal network, such as to determine location and/or function ofparasympathetic postganglionic cell bodies, response to stress tests,distinguish between sensory and motor neuron nerves, or the like.

FIG. 5 shows aspects of access and treatment regions for a target organin accordance with the present disclosure. The target organ is a stomach2401. Also shown is the esophagus 2403, duodenum 2405, aorta 2407, theright gastric artery 2409, the left gastric artery 2411, the splenicartery 2413, the gastric duodenal artery 2415, the right gastroepiploicartery 2417, and the left gastroepiploic artery 2419. Access to one ormore vessels coupled with the stomach may be provided via an ascendingapproach 2421 in the aorta 2407, via a descending approach 2423 in theaorta 2407, or via a descending approach 2425 in the esophagus 2403.

In aspects, one or more neural structures may be monitored and/ortreated on the wall of the stomach 2401, the esophagus 2403, theduodenum 2405, and/or one or more of the vessels coupled thereto. Inaspects, a procedure may be applied in the vicinity of one or more zones2431, 2435, 2437, 2439, 2441, 2443, 2445, 2447 so as to treat aneurological disorder, function, etc. associated with the target organ2401.

In aspects, a procedure and/or selective treatment may be applied to aneural structure, an afferent nerve, an efferent nerve, one or moresympathetic nerves (SNS), or the like in the vicinity of zones 2431,2433, 2435, 2437, 2439, 2441, 2443, 2445, 2447 and/or parasympatheticnerves (PNS) in the vicinity of zones 2433, 2437, 2445, 2447. Inaspects, a treatment may be applied selectively to SNS or PNS in orderto balance a regulatory imbalance in the activity there between, or tocreate an imbalance in activity there between in order to augmentfunction of the target organ, etc.

FIG. 6 shows aspects of access and treatment regions for a target organin accordance with the present disclosure. The target organ shown is afemur bone 2501 (i.e., a representative non-limiting example of a longbone). The femur 2501 generally includes a diaphysis, metaphysis, andepiphysis regions. The treatment may be directed towards a bone relatedhomeostatic function (e.g., osteoblast production), and/or one or moreneural structures coupled with a tumor within one or more of theregions. The femur 2501 includes regions of compact bone 2510, spongybone 2520, and a medullary cavity 2515 in which spongy bone 2520 isinnervated with nerves, and vascularized with associated blood vessels.Exemplary epiphyseal arteries and veins 2520 a, 2520 b, metaphysealarteries and veins 2525 a, 2525 b, and a nutrient artery and vein 2530are highlighted. A system in accordance with the present disclosure maybe sized and dimensioned such that a distal tip thereof may be advancedalong an access point into one or more of the epiphyseal, metaphyseal,or nutrient arteries or veins 2520 a, 2520 b, 2525 a, 2525 b, 2530 totreat one or more regions of the femur 2501.

In aspects, one or more neural structures may be monitored and/ortreated on one or more walls of the epiphyseal artery/vein 2520 a, 2520b, metaphyseal artery/vein 2525 a, 2525 b, and/or the nutrientartery/vein 2530, within the medullary cavity 2515, within one or moresites of the spongy bone 2520, near to the foramen of the femur 2501,within the periosteal space of the femur 2501, and/or one or more of thevessels coupled thereto. In aspects, a procedure may be applied in thevicinity of one or more zones 2535, 2537, 2539, 2541, 2543 so as totreat a neurological disorder, a tumor, pain signals sent between thetarget organ 2501 and the body, treatment of neural receptors, ahomeostatic function, etc. associated with the femur 2501.

In aspects, a procedure and/or selective treatment may be applied to aneural structure, an afferent nerve, an efferent nerve, one or moresympathetic nerves (SNS), parasympathetic nerves (PNS), motor nerves,receptors, and/or the like in the vicinity of zones 2535, 2537, 2539,2541, 2543. In aspects, a treatment may be applied selectively to SNS orPNS in order to balance a regulatory imbalance in the activity therebetween, or to create an imbalance in activity there between in order toaugment one or more functions of the femur, etc. In aspects, theprocedure may be used to treat pain associated with bone cancer, toaugment the microenvironment around a bone cancer tumor so as to alterthe growth rate thereof, to adjust the production rate of osteoblasts,to alter the bone density, or the like.

FIGS. 7a-7c show aspects of methods for treating and/or assessingfunction of a neural structure in accordance with the presentdisclosure. FIG. 7a illustrates aspects of a method for modulating orassessing neural traffic in accordance with the present disclosure. Themethod includes accessing one or more target sites within a body,stimulating, sensing, or ablating the nerves, augmenting neuralactivity, treating the afferent nerves and/or receptors, and optionallyevaluating the afferent nerve activity post treatment to determine ifthe traffic has been modulated. In aspects, the evaluation may beperformed by comparing a nerve activity metric before and aftertreatment (e.g., a change in integrated activity level, a change inphasic response such as a shift from a biphasic polarity to a monophasicpolarity, a change in action potential firing rate, a change in thespectral content of the firing, etc. associated with the local neuraltissues). In aspects, the method may include varying a pressure appliedto the afferent nerves and/or receptors and monitoring afferent nerveactivity during such changes in applied pressure (i.e., monitoringactivity during a variable pressure compression block).

Additionally, alternatively, or in combination with the monitoring ofelectrophysiological activity, the method may include monitoring one ormore physiologic parameters in accordance with the present disclosureand assessing changes in the parameters before, during, or for a periodof time following application of a procedure to the target tissues.

One or more of the steps may be completed with a guidewire or surgicaltool in accordance with the present disclosure.

FIG. 7b shows aspects of a method for treating one or more neuralstructures in a periosteal space in a bone in a subject. The methodincluding accessing the periosteal space of the bone (e.g., via one ormore vessels coupled thereto), optionally monitoring activity in one ormore regions around the periosteal space, treating the nerves, andassessing based on a change in the activity if the treatment wassuccessful. In aspects, the assessment may be determined based on achange in activity level (e.g., pulses per unit of time, drop out ofpulses associated with a particular nerve type, changes in trafficassociated with a neural circuit biorhythm, etc.), a shift in thepolarity of the signals (i.e., a transition from a biphasic signalrelated to multi-directional traffic near the vessel, to a monophasicsignal related to changes more representative of a uni-directionaltraffic near the vessel), a drop off in periodic behavior in thecaptured signals, or the like. In aspects, the, assessment may bedetermined by combining and/or comparing activity measured at multiplesites around the periosteal space, associated vessels, or the like. Suchcomparison may include assessing a change in coherence between twosignals collected from different nearby sites, from a change in onesignal with respect to the other signal collected from nearby sites, achange in a representative transfer function representative of acorrelation between the traffic at one site and the other site, etc.

The assessment may include determining if a change in one or morehomeostatic functions of the organ have changed in a desired direction,if the response of the neural traffic to a stress test has changed asdesired by the therapy, assessing if the subject feels the same,increased, or decreased pain compared with an assessment made before theprocedure. If the treatment has been finished, complete the procedure,pull out any system component in the subject, etc. otherwise, monitoractivity, continue with treatment, and/or move to a new treatment sitein the vicinity of the bone (i.e., exemplary organ).

FIG. 7c illustrates a method for assessing the neural structures in thevicinity of a target organ. The method includes accessing (i.e., such ascommunicating with) the nerves associated with the target organ, diseasestate to be treated, etc. The method may include monitoring an initialactivity level, signal character, periodic element to a signal, afferentor efferent traffic proportion of the neural traffic, etc. The methodmay include monitoring such activity or metrics associated there withduring a stress test as applied to the organ, or subject as a whole. Themethod may include generating and/or analyzing a metric associated withthe change in the monitored activity and determining a suitability ofthe subject for performing a surgical procedure, determining aproportion of nerve types amongst the captured responses, determining ifthe nerves require treatment, determining the influence of the stressoron the locally measured electrophysiological activity, or the like.

The method may include modulating a functionality of, neural activityfrom, afferent activity from, or the like of the target organ of asubject, the method may include selectively stimulating and/or stressingone or more regions of the target organ and monitoring the physiologicresponse at one or more sites nearby and/or systemically to thestimulus/stress. In aspects, the stimulus/stress response may be used toidentify regions of the target organ that are suitable forneuromodulation to treat a particular condition. In aspects, the methodmay include selectively treating one or more sites within or in thevicinity of the target organ. In aspects, the method may includemonitoring activity and/or local physiologic response to the treatmentat one or more of the sites to determine the extent of the procedure, toevaluate when the procedure has been completed, to decide whether or notto continue with the procedure, etc. The method may include ablating aportion of the organ, or a neurological structure coupled thereto, inaccordance with the present disclosure. In aspects, the method mayinclude using a guidewire and/or surgical device in accordance with thepresent disclosure to perform one or more of the above steps.

In aspects, an ablation may be performed so as to minimize damage tosurrounding tissues. The ablation may include delivering energy to thelocal tissues in an amount just sufficient to induce irreversible damageto one or more adjacent nerves, but not in an amount sufficient toirreversibly damage other surrounding tissues.

In aspects, the method may include dragging one or more electrode arraysin accordance with the present disclosure along a lumen in the vicinityof the target organ in order to locate neurological features of interestassociated with the organ, locate one or more baroreceptors, mapactivity thereof, map functional changes thereof due to application of atreatment or stress thereto, evaluate the function thereof, and/or treatone or more such structures.

FIGS. 8a and 8b show aspects of access and treatment regions for atarget organ in accordance with the present disclosure. The target organshown is a coxal bone 2601 a (i.e., a representative non-limitingexample of a complex bone structure). FIG. 8a illustrates an exopelvicview of half of a coxal bone 2601 a and the vasculature providing bloodto the coxal bone 2601 a. Also illustrated are sections A, B, C of thecoxal bone 2601 a (roughly corresponding to the illium, acetabulum, andischium), which may be accessed by different vasculature respectively.Section A may be accessed via the superior gluteal artery 2605, thesuperficial branch of the superior gluteal artery 2607, the deep branchof the superior gluteal artery 2609, the deep superior gluteal artery2611, deep inferior gluteal artery 2613, and/or the artery of theacetabulum 2615. The nerves associated with sites in section A may betreated by applying a system or method in accordance with the presentdisclosure to zone 2620 or a site in the vicinity thereof. Section B maybe accessed via the pudendal artery 2617 or a branch thereof, or theartery of the ischium 2619. The nerves associated with section B may betreated by applying use of a system or method in accordance with thepresent disclosure to zone 2630 or a site in the vicinity thereof.Section C may be accessed via the obturator artery 2623 and a treatmenttherefor applied in the region of zone 2640.

In general, it can be seen from FIG. 8a that the treatment may beprovided along any of the indicated arteries, but that an improvedtherapy in terms of maximizing localization of the treatment, whileminimizing collateral involvement of other nerves in the body may beperformed near enough or in a deep enough branch, such that the branchunder consideration provides only the region of the organ to be treated,while not getting so close to the organ, or within the organ, such thata high proportion of nerves are no longer within the reach of thetreatment for a given site along the selected vessel.

FIG. 8b illustrates an endopelvic view of half of a coxal bone 2601 band the vasculature providing blood to the coxal bone 2601 b. Alsoillustrated are sections D, E, F of the coxal bone 2601 b (roughlycorresponding to the ischium/pubic body/acetabulum, the posterior iliacspine, and the iliac crest), which may be accessed by differentvasculature respectively. Section D may be accessed via the illiolumbarartery 2641. The nerves associated with sites in section D may betreated by applying or using a system or method in accordance with thepresent disclosure to zone 2650 or a site in the vicinity thereof.Section E may be accessed via the obturator artery 2643 or a branchthereof, or the pudendal artery 2645. The nerves associated with sectionE may be treated by applying or using a system or method in accordancewith the present disclosure to zone 2660 or a site in the vicinitythereof. Section F may be accessed via the deep circumflex iliac artery2647 and a treatment therefor applied to one or more nerves in theregion of zone 2670 or a site in the vicinity thereof.

In aspects, one or more neural structures may be monitored and/ortreated on one or more walls of the arteries or veins 2605, 2607, 2609,2611, 2613, 2615, 2617, 2619, 2623, 2641, 2643, 2645, 2647, within themedullary cavity of the coxal bone 2601 a, 2601 b, within one or moresites of the spongy bone, near to the foramen of one or more of thearteries/veins 2605, 2607, 2609, 2611, 2613, 2615, 2617, 2619, 2623,2641, 2643, 2645, 2647 into the coxal bone 2601 a, 2601 b, within theperiosteal space of the coxal bone 2601 a, 2601 b, one of more of thesections A, B, C, D, E, F, and/or one or more of the vessels coupledthereto. In aspects, a procedure may be applied in the vicinity of oneor more zones 2620, 2630, 2640, 2650, 2660, 2670 so as to treat aneurological disorder, a tumor, pain signals sent between one or moreregions of the coxal bone 2601 a, 2601 b and the body, treatment ofneural receptors, a homeostatic function, etc. associated with the coxalbone 2601 a, 260 b.

In aspects, a procedure and/or selective treatment may be applied to aneural structure, an afferent nerve, an efferent nerve, one or moresympathetic nerves (SNS), parasympathetic nerves (PNS), motor nerves,receptors, and/or the like in the vicinity of zones 2620, 2630, 2640,2650, 2660, 2670. In aspects, a treatment may be applied selectively toSNS or PNS in order to balance a regulatory imbalance in the activitythere between, or to create an imbalance in activity there between inorder to augment one or more functions of the femur, etc. In aspects,the procedure may be used to treat pain associated with bone cancer, toaugment the microenvironment around a bone cancer tumor so as to alterthe growth rate thereof, to adjust the production rate of osteoblasts,to alter the bone density, or the like.

In aspects, a method in accordance with the present disclosure mayinclude inserting the distal tip of a device in accordance with thepresent disclosure into a vessel coupled to the tumor. In aspects, themethod may include advancing the tip of the device along the vessel suchthat the tip may interact with a wall of the vessel sufficiently near tothe tumor so as to selectively interact with the neural structurescoupled specifically to the tumor. Such positioning may be advantageousto so as to minimally influence other neural structures in the bodywhile interacting with those coupled to the tumor. In one non-limitingexample related to the treatment and/or pain reduction of a bone cancertumor located in the diaphysis region of a femur, the method may includeadvancing the tip of the device along an artery or vein within the bodyso as to reach the nutrient artery and/or vein near to the femur (i.e.,sufficiently near such that the nerves running alongside the arteryand/or vein are primarily coupled with the femur as opposed to nearbymuscles, skin, peroneal nerves, or the like). In aspects, the tip may beadvanced along the nutrient artery so as to enter a branch dedicated tothe femur, so as to interact with the vessels near to the periosteum ofthe femur, near to the foramen where the nutrient artery or vein entersthe femur, to pass within the medullary cavity of the femur, or thelike. In aspects, a method to treat a tumor and/or pain associatedtherewith in the epiphysis and/or metaphysis of a femur may includeaccessing an epiphyseal and/or metaphyseal artery with a tip of a devicein accordance with the present disclosure.

According to aspects there is provided a system for treating nervescoupled to a bone of a subject, the system including a micro-tool inaccordance with the present disclosure, the micro-tool including a tipsized and dimensioned for placement within a nutrient, epiphyseal,and/or periosteal vessel, artery, or vein coupled to the bone, themicro-tool tip including means for ablating tissues in the vicinity ofthe vessel in accordance with the present disclosure.

In aspects, the micro-tool tip may include a sensing tip in accordancewith the present disclosure, the sensing tip configured to measure oneor more of an electrophysiological signal, a neural activity, anafferent neural signal, or the like associated with one or more nervesin the vicinity of the vessel to produce a sensory signal relatedthereto. In aspects, the micro-tool tip may be configured to provide acontrolled ablation to one or more of the nerves, while substantiallypreserving tissues surrounding the nerves. In aspects, the micro-tooltip may include a substance delivery needle for providing a drugsubstance to one or more of the nerves to perform the ablation. Inaspects, the micro-tool tip may include an energy delivery means, forproviding an ablating current, ultrasound energy, high intensity focusedultrasound (HIFU), MR guided HIFU, thermal energy, cryogenic change,etc. to one or more of the nerves. In aspects, the system may include asignal conditioning circuit and a processor for identifying the presenceand/or characterizing one or more of the nerves, to generate a feedbacksignal therefrom, and to coordinate the energy or substance deliverybased upon the feedback signal.

In aspects, the micro-tool tip may have a characteristic diameter ofless than 1 mm, less than 0.5 mm, less than 0.25 mm, or the like tofacilitate placement into the vessel.

In aspects, the micro-tool tip may include one or more electrodes inaccordance with the present disclosure. One or more of the electrodesmay be sized and dimensioned to measure the signal, and/or one or moreof the electrodes may be sized and dimensioned to stimulate and/orablate one or more of the nerves. In aspects, the micro-tool tip mayinclude a plurality of electrodes, each electrode configured for sensingan electrophysiological signal in accordance with the present disclosurein the vicinity thereof, the electrodes electrically isolated from eachother such that the collection of locally collected signals may be usedto determine activity over region of tissues in the vicinity of thevessel. In aspects, a plurality of electrodes configured for sensing maybe coupled to a source, the source configured to deliver a stimulatoryor ablation current collectively through the electrodes into theadjacent tissues for interacting with one or more of the nerves. Inaspects, the source may be configured such that a current may besubstantially directed radially, circumferentially, and/or axially alongthe vessel wall to interact with one or more of the nerves. In aspects,the micro-tool tip may include a plurality of electrodes configured forsensing, the electrodes situated along the micro-tool tip so as tomonitor local activity axially along the vessel.

In aspects, the micro-tool tip may include a reference electrodeconfigured for sensing electrophysiological activity over a larger areathan the other sensing electrodes, one or more of the sensing electrodescompared against the reference electrode to form one or more of thesignals. In aspects, the source may be configured to ablate the nervesin concert with the sensing, such that the ablation stops in response toa change in one or more of the sensory signals.

In aspects, there is provided, a method for treating nerves coupled to abone in a subject, the method including ablating, and/ordefunctionalizing one or more nerves coupled to the bone in the vicinityof the periosteal space of the bone, and/or in the vicinity of anutrient, epiphyseal, and/or periosteal artery or vein coupled to thebone.

In aspects, the method may include delivering a micro-tool in accordancewith the present disclosure through the nutrient, epiphyseal, and/orperiosteal artery or vein to interface with the nerves, at least aportion of the ablating and/or defunctionalizing performed by themicro-tool. In aspects, the method may include determining the locationof a tumor in the skeleton of the subject and planning a surgicalapproach to reach one or more vessels coupled to the tumor, or coupledto a region of the bone in which the tumor is located. In aspects, themethod may include determining the afferent and/or the efferent neuraltraffic from the electrophysiological signals via an algorithm inaccordance with the present disclosure.

In aspects, the method may include monitoring the polarity of one ormore signals to determine if the signals predominantly includepredominantly afferent or efferent neural traffic. In aspects the methodmay include counting positive facing action potentials per unit timeassociated with monitored neural traffic, counting the negative facingaction potentials per unit time associated with the monitored neuraltraffic, and determining a proportion of positive facing actionpotentials per unit time from the total number of action potentials. Themethod may include deriving a metric to determine whether the overalltraffic is predominantly efferent or afferent in nature, the metricrelated to the proportion. In aspects, the method may include monitoringthe electrophysiological signals during a stress test in accordance withthe present disclosure to determine the type and/or function of one ormore of the nerves.

In aspects, a system and/or method in accordance with the presentdisclosure may be used to treat bone cancer, to reduce, stop, or reversea rate of tumor growth, and/or to reduce or stop cancer related pain. Inaspects, a system and/or method in accordance with the presentdisclosure may be used to treat osteoporosis, and/or to augment bonedensity of one or more bones in a subject. By bone is meant one or morebones of the skeleton of a subject. Some non-limiting examples of bonesinclude femur, coxal, sacrum, vertebrae, ribs, humerous, ulna, radius,and tibia.

Depending on the location of the tumor within the bone, the approach fortreating the nerves may be directed along an artery or vein feeding theepiphysis region of the bone, the joint, cartilage in the joint, thediaphysis of the bone, the periosteal region of the bone, or the like.In aspects, the micro-tool may be inserted along the artery or vein towithin the margin of the bone, and ablation may be performed along thevessel walls to treat the nerves at these sites.

In aspects, a micro-tool in accordance with the present disclosure maybe inserted along the artery or vein in the periosteal region of thebone and may be used to treat the nerves as they approach the bone alongsuch vessels.

A treatment for increasing bone density within one or more bones in asubject may include ablating the afferent and/or sympathetic nervesinnervating a bone in a subject. The method may include ablating one ormore nerves in the vicinity of the epiphyseal, nutrient, and/ormetaphyseal forma or vessel (artery/vein) near to the bone. The methodmay include ablating the nerves at one or more sites along the pathbetween the nerves and/or nutrient vessels separating from the parentplexus and the branches serving substantially just the bone in question.Some non-limiting examples of parent plexuses (dependent on theparticular bone under treatment) include the peroneal nerve plexus,ulnar nerve plexus, a lumbar plexus, obturator plexus, superior glutealnerve plexus, inferior gluteal nerve plexus, tibial nerve plexus,accessory obturator plexus, pudental nerve plexus, or the like. Thetreatment site may be selected such that the branch from the parentplexus is near to or into a region of marrow in the bone.

In a method in accordance with the present disclosure, a stress test maybe applied to determine if the distal tip is properly placed fortreatment of the nerves substantially innervating only the targetbone/organ. In aspects, the stress test may include applying a touch,heat, etc. to a lower extremity, stimulation to a muscle, etc. whilemonitoring neural traffic along the wall of a target vessel. If a strongresponse is seen at the sensing site, advance the distal tip furtheralong towards the bone/organ before testing again. If the distal tipdoes not register a response from the seemingly unrelated stimulus orstress, treat the nerves at that site.

In accordance with the present disclosure, there is described use of amethod and/or system in accordance with the present disclosure to alterbone pain (i.e., associated with a recurring injury, osteoporosis, bonecancer, etc.), bone density, bone tumor progression, and/or fertility ina subject. In aspects, ablation of one or more nerves through the wallof a nutrient artery or vein in a subject may be used to treat bonepain, alter bone tumor growth, alter bone density, and/or alter afertility state of a subject.

Generally speaking, the broad distribution of innervation to bones mayexplain why pain originating from the joint presents in many ways, withvariable and complex referral patterns for individual patients. Thecoxal bone and the medullary cavity of the coxal bone are innervatedwith nerves that travel along with the arteries and veins servingvarious regions of the bone (e.g., the ilium, pubis, and acetabulum).Such innervation travels alongside the femoral artery, the superior andinferior gluteal arteries, the artery of the acetabulum, pudendalartery, artery of the ischium, obturator artery, and branches thereof.The innervation to the various regions of the coxal bone stems from thefemoral nerve, obturator nerve, sciatic nerve, etc.

In aspects, a system or method in accordance with the present disclosuremay be configured to provide therapy to one or more neural structures inthe vicinity of one or more such arteries, generally in the vicinity ofthe periosteum of the coxal bone. In aspects, the location of a tumorwithin the coxal bone may be identified (i.e., via a sensing system ormethod in accordance with the present disclosure, via an imagingmodality, etc.). Once the location is identified, a strategy to reachthe nerves coupled to that region of the coxal bone may be formulated,as outlined in the FIGS. 8a and 8b . As can be seen from the FIGS. 8aand 8b , target regions for treatment of the nerves coupled to the boneare generally coupled to branches of the parent arteries. In aspects,the treatment may be performed on a branch of an artery or vein that isentirely coupled with the intended bone (i.e., as opposed to treatingthe parent vessel, which may include a plurality of additional neuralstructures, not related to the target region of the target bone). Suchan approach may be used to provide an effective and highly selectivetreatment with a minimum of treatment volume, and while minimizing sideeffects, affecting other nearby neural circuits, etc.

FIGS. 9a-9c show aspects of a device 900 in accordance with the presentdisclosure. FIG. 9a shows the device 900, shaped and dimensioned forplacement into an organ, a vessel, a foramen, etc. each in accordancewith the present disclosure. The device 900 includes a sensing tip 910which is positioned within a region 907 (i.e., in this along a nutrientartery 12 near the foramen of a long bone 10) for purposes of treatment,monitoring, diagnostics, etc. A region 907 defined in the vicinity ofthe sensing tip 910 may be coupled with the sensing tip 910 during aprocedure (e.g., for purposes of monitoring, stimulating, treating,ablating, delivering a substance to, etc. tissues in the vicinity of theregion 907). The device 900 has been inserted endovascularly,percutaneously, etc. into a lumen in the body in accordance with thepresent disclosure and directed to the monitoring site near the longbone 10. In the example shown, the device 900 has been directed alongthe nutrient artery 12 (alternatively along a nutrient vein 14,epiphyseal artery/vein, metaphyseal artery/vein, or the like, etc.) suchthat the tip 910 of the device 900 is placed in intimate contact withone or more electroactive anatomical sites there within. In aspects, thedevice 900 may be placed such that the tip 910 is oriented within thelumen of a vessel (e.g., an artery, a vein, nearby or into the bone,etc.) for obtaining physiologic information therefrom.

As shown in FIG. 9a , the tip 910 is placed such that thesensing/treatment elements associated therewith are positioned so as totreat the targeted nerves without causing extensive damage to the targetorgan (e.g., in this case a femur bone). In aspects, the tip 910 may bepositioned near the foramen of the bone, near to the foramen but outsideof the bone perimeter, etc. In aspects, the tip 910 may be positionedjust within the bone, the energy/chemical delivering portion of the tip910 positioned so as to interact with the nerves near the foramen, theperiosteal space, a joint, an epiphyseal space, a metaphyseal spacevesicular, etc.

In aspects, the device 900 (e.g., a guidewire, a microtool, a catheter,etc.), placed nearby and/or within the bone margin may be arranged so asto monitor electrophysiological activity during an associated stimulusevent, surgical procedure/event, follow up procedure, stress test, etc.Such events may include a change in bone stress (e.g., as induced by achange in posture, introduction of bolus of fluid, altering bloodpressure systemically, etc.), introduction of a vasodilator (e.g.,bradykinin, etc.), inducing a thermal change (e.g., changing a roomtemperature, introducing a hand into cold or warm water, cooling orwarming the blood, etc.), performance of a surgical procedure inaccordance with the present disclosure, combinations thereof, or thelike. The local electrophysiological response to such stimulus may be anindicator of the function of bone receptors, sensitivity to bone pain,traffic relating to bone pain, extent of cancer damage to the bone, mayhelp to quantify the state of the sympathetic nervous system in thesubject, may be used to determine or predict the extent that a subjectmay respond to a procedure, etc. In aspects, the stimulus may cause achange in afferent signal activity from nerves innervating a spongybone, a periosteal space, a joint, an epiphyseal space, a metaphysealspace, etc. Such activity may be monitored at a second location near aneural plexus along the femoral artery, near to the spine, or elsewherein the body. The presence, change in, or absence of such signals at thesecond location may be indicative of the health of the neurologicalinterconnection there between (e.g., the state of the nerves locatedbetween the two sites, the extent of a neuromodulation procedure, etc.).

The device 900 may be connected to a controller 920 (not explicitlyshown) for purposes of capturing signals from the tip 910 thereof. Thesensing tip 910 may include one or more sensors and/or electrodes, eachin accordance with the present disclosure. The device 900 may includeone or more electrical interconnects (not explicitly shown) at theproximal end for interfacing with the controller 920.

Such a configuration may be advantageous for monitoring key physiologicinformation relating to a neuromodulation stimulus, a stress test, asurgical outcome, disease state, a surgical follow up, a neuroendocrinediagnostic, a neurological response to one or more of the above, etc. Inaspects, such information may be used for purposes of diagnosing adisease within a subject, for determining the outcome of a stimulus orsurgical procedure, for predicting the outlook of a subject after asurgery or a procedure, for predicting a subject's response to orsuitability for a neuromodulation therapy, etc.

FIG. 9b shows a schematic of a sensing guidewire 900 in accordance withthe present disclosure. The guidewire 900 includes a sensing tip 910 atthe distal end thereof. The sensing tip 910 may include one or moresensors and/or electrodes each in accordance with the presentdisclosure. The guidewire 910 may also include one or more connectors940 located at the proximal end thereof. The connectors 940 may bedimensioned and configured to interface with an interconnection module935 or a controller 920. Although shown separately, the interconnectionmodule 935 and the controller 920 may be integrated into a single unit.In aspects, a system in accordance with the present disclosure mayinclude both an interconnection module 935 and a controller 920 coupledtogether by a cable 945.

The guidewire 900 may include one or more leadwires and/or fibers toconnect elements in the sensory tip 910 to the connectors 940 thereof.In aspects, such leadwires may be constructed from one or more materialsknown in the art. In aspects, the leadwires and/or fibers may beconstructed from MRI compatible materials (e.g., resistive wires, carbonfibers, etc.) so as to minimize heating during use in MRI guidedsurgical procedures.

In aspects, the optional interconnection module 935 may include one ormore preamplifiers, multiplexers, switching networks, etc. each inaccordance with the present disclosure. Such a configuration may beadvantageous to minimize the length of leadwires between the sensing tip910 and the first signal amplification stage (i.e., a preamplifier inthe interconnection module 935).

In aspects, the guidewire 900 may include one or more microcircuits 930embedded therein. The microcircuits 930 may be coupled with one or moreelements within the sensing tip 910 as well as coupled to the connectors940. The microcircuits 930 may be dimensioned and configured to providesuitable preamplifier functionality, multiplexing operations, digitalcommunication hardware, etc. in order to improve signal integrity fromone or more elements within the sensing tip 910, to reduce lead wirecount, etc. In aspects, the microcircuits 930 may be coupled to elementsof the sensing tip 910 using an ultra-high density interconnecttechnology as known in the art and in accordance with the presentdisclosure.

In aspects, the microcircuit 930 may be implemented in an applicationspecific integrated circuit, as one or more bare die chipsets, flipchips, ultrafine pitch ball grid array mounted chipsets, chip scalepackages, ultra-fine blind via attachment, flexible HDI interconnects,wire bonded bare die, combinations thereof, or the like. In aspects, themicrocircuit 930 may be formed from a thinned silicon die, thinned to athickness of less than 100 μm, less than 50 μm, less than 10 μm, lessthan 5 μm. In aspects, the microcircuit 930 may be provided in anultra-low profile flip-chip, chip scale package, with pitch scaling inthe range of 10-50 μm.

In aspects, an array of microcircuits 930 may be arranged upon asubstrate in accordance with the present disclosure to facilitateinterconnection with the sensing tip 910. The array of microcircuits 930may be arranged along the substrate and dimensioned so as to maintainthe small diameter aspects of the guidewire 900 (i.e., arranged in asingle file linear pattern along a predetermined length of the guidewire900). In aspects, the microcircuit 930 may be encapsulated in a polymerbead, inserted into a protective tube, inserted into the core of aguidewire spring shank, etc.

In aspects, the microcircuit 930 may be coupled with one or morestrengthening members so as to minimize the risk of damage to thecoupling between the microcircuit 930 and the sensing tip 910 or theconnectors 940. In aspects, the strengthening members may be configuredto as to allow for compression, tension, and/or torque transfer throughthe region of the guidewire 900 that includes the microcircuit 930.

In aspects, the controller 920 may include one or more user inputs(e.g., buttons, foot pedals, sliding mechanisms, touch screen displays,etc.) for providing the controller with user guided input so as toadjust signal gain, deploy an aspect of a surgical tool, adjust astimulation parameter, apply a stimulation, combinations thereof, or thelike. In aspects, the controller 920 may include a display for providinga user with information relating to the physiologic signals, outcome ofa procedure, an electrophysiological map, combinations thereof, or thelike.

FIG. 9c shows aspects of methods for using a device 900 (e.g., amicrotool, a catheter, a guidewire, etc.) in accordance with the presentdisclosure. Although the methods describe accessing the parenchyma of anorgan, foramen, organ margin, etc. they could be equally adapted tomeasuring electrophysiological activity in vessels within a body (e.g.,within arteries, veins, etc.), for accessing a miniature lumen withinthe body, etc. A first method 960 for diagnosing a medical condition isdescribed that includes accessing the parenchyma of an organ. Byaccessing the small vessels accessing or within the parenchyma of anorgan is meant coupling a sensor or electrode in accordance with thepresent disclosure with one or more anatomical sites within theparenchyma of an organ, so as to measure, stimulate, and/or treat one ormore sites therefrom. The first method 960 further includes recordingphysiologic activity from the parenchyma of the organ (e.g., with asensor or electrode, a guidewire, a surgical tool, etc. each inaccordance with the present disclosure), and monitoring a trend in thephysiologic signal (e.g., during a stimulation event, during a stresstest, etc.), and/or making a diagnosis or prognosis based upon therecorded signal (e.g., a diagnosis of a disease state associated withlocal physiologic activity in the parenchyma of the organ, making aprognosis relating to an outcome of a disease state associated withactivity in the parenchyma of the organ, etc.).

In aspects, the first method 960 may include one or more additionalsteps in accordance with the present disclosure. In aspects, the firstmethod 960 may include placing an additional tool including one or moresensors and/or electrodes at a remote location (with respect to theorgan) in the body and stimulating the local anatomy at either theremote site or within the parenchyma of the organ and monitoring anevoked response within the parenchyma of the organ or at the remote siterespectively. Such a configuration may be advantageous for elucidatinginformation about the connectivity between the two sites (i.e., relevantto determining if a neuromodulation procedure applied there between hasbeen successful, etc.).

A second method 970 is shown including accessing the parenchyma of anorgan in accordance with the present disclosure. The second method 970may further include recording physiologic activity from the parenchymaof the organ, performing a treatment on the body, recording a change inphysiologic activity, and determining if the treatment was successfullyapplied. In aspects, the second method 970 may include one or moreadditional steps in accordance with the present disclosure.

A third method 980 is shown including accessing the parenchyma of anorgan (alternatively an anatomical site of interest, a vessel, anartery, a vein, an arteriole, a venule, a foramen of a bone, into aspongy bone, into a joint, into a epiphyseal space, a metaphyseal space,etc.), and mapping the electrophysiological activity in the vicinity ofthe anatomical site of interest. The mapping may be provided by sweepinga sensory tip in accordance with the present disclosure over theanatomical site of interest, inserting and then withdrawing the sensorytip, deploying the sensory tip and then dragging and/or rotating thedeployed tip along/around the lumen wall, combinations thereof, and thelike. In aspects, the third method 980 may include displaying the mappedphysiologic information for a user, constructing an anatomical modeltherefrom, directing a surgical robot to perform a treatment therefrom,comparing the map with a previously determined map (e.g., as a means formonitoring the outcome of a procedure, tracking a therapy, etc.),combinations thereof, or the like. In aspects, the method may includeproviding one or more directions to a surgeon and/or a surgical robot toaccess one or more regions of the mapped anatomy, overlaying the presentmap with previously generated maps (so as to evaluate changes infunctionality, activity, etc.), combinations thereof, and the like.

A fourth method 990 is described including accessing an anatomical siteof interest within the parenchyma of an organ, stimulating one or morephysiologic systems in the body, and monitoring the evoked response atthe anatomical site of interest. The fourth method 990 may includeassessing the functionality of the anatomical site of interest, the siteof stimulation (i.e., if the stimulation is of a localized type), or ananatomical site there between. In aspects, the method may includeablating one or more anatomical sites within the body. A device 2110,900 in accordance with the present disclosure may include one or moreelectrodes, chemical delivery elements, etc. configured to performing atreatment on the surrounding tissues, etc. In aspects, one or moremethods in accordance with the present disclosure may be completed, atleast in part, with a device 900 in accordance with the presentdisclosure.

FIG. 9d shows a schematic of a sensing guidewire 902 in accordance withthe present disclosure. The guidewire 902 may include one or more zonessuch as a sensing tip 912, a sensing/ablation/stimulation zone 914,and/or a second sensing zone 932 each located towards the distal endthereof. One or more of the zones may include aspects for sensing,ablating, stimulating, biasing against adjacent tissues, etc. Inaspects, the sensing tip 912 may include one or more sensors and/orelectrodes each in accordance with the present disclosure. In aspects, asecond zone 914 may be configured to bias 937 one or more aspects of theguidewire 902 against an adjacent lumen wall for purposes of couplingthereto (such as to perform a procedure in accordance with the presentdisclosure, etc.). In aspects, a third zone 932 is shown, configured soas to interface with an adjacent lumen wall for purposes of sensing,ablation, stimulation, combinations thereof, or the like.

In aspects, the guidewire 902 may also include one or more connectors942 in accordance with the present disclosure located at the proximalend thereof. The connectors 942 may be dimensioned and configured tointerface with an interconnection module 938 or a controller 922.Although shown separately, the interconnection module 938 and thecontroller 922 may be integrated into a single unit. In aspects, asystem in accordance with the present disclosure may include both aninterconnection module 938 and a controller 922 coupled together by acable 947.

In aspects, the optional interconnection module 938 may include one ormore preamplifiers, multiplexers, switching networks, etc. each inaccordance with the present disclosure. Such a configuration may beadvantageous to minimize the length of leadwires between the sensing tip912 and the first signal amplification stage (e.g., a preamplifier inthe device 900, the vicinity of the sensing tip 912, the interconnectionmodule 938).

In aspects, the guidewire 902 may include one or more microcircuitsembedded therein (herein embedded within one or more of the zones 912,914, 932). The microcircuits may be coupled with one or more elementswithin the sensing tip zone 912 as well as coupled to the connectors942. The microcircuits may be dimensioned and configured to providesuitable preamplifier functionality, multiplexing operations, digitalcommunication hardware, etc. in order to improve signal integrity fromone or more elements within the sensing tip zone 912, to reduce leadwire count, etc. In aspects, the microcircuits may be coupled toelements of the sensing tip zone 912 using an ultra-high densityinterconnect technology as known in the art and/or in accordance withthe present disclosure. In aspects, one or more of the zones 912, 914,932 may be configured so as to interface with an adjacent anatomicalfeature along which a treatment is desired. Information and/or treatmentprovided by each zone may be used to determine effective delivery oftreatment to a region along the anatomical feature (i.e., physiologicsensing and/or stimulation provided at sites within zones 912 and 932may be used to determine the effectiveness of a neuromodulation therapyprovided to the adjacent tissues in the vicinity of zone 914). Inaspects, a therapeutic, stimulatory, and/or sensing configuration may becoupled between zones 912, 914, 932. In aspects, one or more steps of amethod in accordance with the present disclosure may be performed withone or more zones 912, 914, 932 of a guidewire 902 in accordance withthe present disclosure.

The connectors 942 may be dimensioned and configured to interface withan interconnection module 938 or a controller 922. Although shownseparately, the interconnection module 938 and the controller 922 may beintegrated into a single unit. In aspects, a system in accordance withthe present disclosure may include both an interconnection module 938and a controller 922 coupled together by a cable 947. In aspects, theoptional interconnection module 938 may include one or morepreamplifiers, multiplexers, switching networks, etc. each in accordancewith the present disclosure. Such a configuration may be advantageous tominimize the length of leadwires between the sensing tip 912 and thefirst signal amplification stage (i.e., a preamplifier in theinterconnection module 938).

FIGS. 10a-10n show aspects of sensing tips 910, and/or zones 912, 914,932 associated with a device 900, 902 (a device, a catheter, aguidewire, etc.) each in accordance with the present disclosure. FIG.10a shows aspects of a device 1001 including one or more sensors orelectrodes 1002 located at the distal tip thereof. In aspects, theelectrodes 1002 may be arranged in patterns around the circumference ofthe tip so as to contact a lumen wall if the guidewire 1001 isintroduced deep enough into the lumen so as to bottom out (i.e., as thelumen diameter shrinks distally heading into the organ). The electrodes1002 may be connected to a controller 1005, a preamp, a microcircuit, aconnector, or the like in accordance with the present disclosure. Suchinterconnection may be provided by one or more leadwires 1004 arrangedalong the length of the device 1001. In aspects, one or more of theleadwires 1004 may be integrated into the walls or jacket of the device1001. In such configurations, the leadwires 1004 may be helicallyintegrated, and/or braided into the walls or jacket, or equivalentlythreaded, coextruded, plated, shrink wrapped, or pultruded within thewalls of the device 1001 (i.e., or equivalently threaded through one ormore microlumen within the wall of the device 1001). In aspects, thedevice 1001 may have a distal tip diameter 1003 of less than 3 mm, lessthan 2 mm, less than 1 mm, less than 0.5 mm, less than 0.25 mm, or thelike to facilitate placement into the vessel.

The electrodes 1002 may be formed in accordance with the presentdisclosure. In aspects, the electrodes 1002 may be formed directly fromthe tips of the one or more leadwires 1004. The tips of the leadwires1004 may be formed into microelectrode elements, with predeterminedexposed areas and tip profiles, suitable for monitoringelectrophysiological activity at the site of interest. In aspects, thepredetermined exposed areas may be designed so as to lean towards singleunit recordings (e.g., electrode area less than 250 square micrometer(μm²), less than 150 μm², less than 100 μm²), multi-unit recordings(e.g., electrode area of greater than 500 μm², greater than 1000 μm²,greater than 2000μ²), and large area or reference field recordings(e.g., electrode area greater than 10,000 μm², greater than 1,000,000μm², or the like). In aspects, the electrodes 1002 may be treated so asto alter the impedance thereof, during use. In aspects, the electrodesmay be processed so as to increase the capacity thereof such as viaconversion to, plating of, or augmentation with an electric energystorage (EES) material, an intercalating material, surface areaincreasing process, a plating process, combinations thereof, or thelike. In aspects, each electrode 1002 may be configured with a profilesuited for accessing the anatomy of interest (e.g., a needle-likestructure, an embossed structure, a whisker like structure, a dendriticstructure, etc.).

FIG. 10b illustrates aspects of a sensing tip of a guidewire 1006 with adeployable tip array 1008 arranged near to or at the distal tip thereof.Optionally, the guidewire 1006 may include a jacket 1007 arranged alongthe length thereof. The jacket 1007 may be configured so as to slidealong a core structure, the core structure supporting the deployable tiparray 1008. Thus, retraction of the jacket (or equivalently protrusionof the core structure) may be used to deploy the elements of thedeployable tip array 1008 once the tip of the guidewire 1006 has beendelivered to an anatomical site of interest. The deployable tip array1008 may include one or more microfingers 1010 in accordance with thepresent disclosure. Each microfinger 1010 may include one or moresensors or electrodes in accordance with the present disclosure. In FIG.10b , a guidewire 1006 is shown with an array of microfingers 1010, eachequipped with a microelectrode 1009 upon the distal tip thereof. Themicroelectrodes 1009 and microfingers 1010 may be configured so as tobias towards a lumen wall upon deployment, or configured so as topenetrate the lumen wall upon deployment or during a penetratingmaneuver (e.g., pushing the deployed tip array 1008 forward along thelumen wall, etc.). In aspects, the microfingers 1010 may be actuated soas to facilitate deployment (e.g., via an electroactive,electrochemical, mechanical, and/or thermomechanical activation means).In aspects, the microfingers 1010 may be one-time deployable via abiodegradable mechanism (e.g., dissolution of an adhesive bindingelement, a thermally activated material, etc.).

In aspects, one or more of the microfingers 1010 may be shaped such thatit forms the desired shape upon deployment (subject to the dimensions ofthe local anatomy). In aspects, the microfingers 1010 may be configuredto form an umbrella like structure, a basket like structure, a helicalstructure, a star like structure, a porcupine like structure, etc.

One or more elements of the sensing tip may be interconnected with acontroller 1011, preamp, microcircuit, circuit, a connector, or the likein accordance with the present disclosure.

FIG. 10c shows aspects of a sensing tip of a guidewire 1015 inaccordance with the present disclosure. The sensing tip includes aj-curved segment 1016 which may be configured with a subminiature bendradius. In aspects, the j-curved segment 1016 may be formed with aradius of less than 4 mm, less than 3 mm, less than 1 mm. The sensingtip may include one or more electrodes 1017, 1018. As shown in FIG. 10c, the sensing tip may include one or more microelectrodes 1017 and oneor more reference electrodes 1018 (optional). The microelectrode 1017may be exposed to the surroundings over a subset of the overall tip area(e.g., over an area most likely to bias against a lumen wall duringinsertion, over a region facing away from the axis of the j-curvesegment 1016, etc.). In aspects, the reference electrode 1018 may beformed by exposing and/or processing a segment of the guidewire 1015(e.g., removing an insulating coating therefrom, plating a materialthereto, swaging a tube onto the guidewire segment, etc.). Theelectrodes 1017, 1018 may be coupled to a connector and/or a controller1020, preamp, microcircuit, circuit, a connector, or the like inaccordance with the present disclosure.

The j-curved segment 1016 may be advantageous to maintain contact withthe walls of a lumen during a placement procedure. In aspects, thej-curved segment 1016 may be dimensioned with a predetermined radius andconfigured with a predetermined stiffness such that the electrodes 1017,1018 may consistently contact the walls of vessels with a characteristicdiameter within a predetermined range (e.g., 2-8 mm, 1-4 mm, 0.5-2 mm,etc.). The j-curved segment 1016 may also be configured so as to bias1019 the electrodes against the wall of a lumen during a study. Inaspects, the j-curved segment 1016 may include one or more strainmeasuring elements (e.g., a strain gauge, a piezoresistive material,etc.) configured to measure the diameter of the lumen into which theguidewire 1015 has been placed.

FIG. 10d illustrates aspects of a sensing tip of a sensing guidewire1021 in accordance with the present disclosure. The guidewire 1021includes a pushable core 1022 or equivalently a retractable sheath 1023configured so that the core can be deployed once the guidewire 1021 hasbeen directed to an anatomical site of interest. In aspects, one or moreof the tip configurations disclosed herein may be attached to thepushable core 1022 in order to construct a sensing guidewire 1021 with adeployable 1022 a tip structure (e.g., with a deployable tip array, abasket arrangement, etc.).

In aspects, the core 1022 may be coupled with a controller 1025, preamp,microcircuit, circuit, a connector, or the like each in accordance withthe present disclosure.

FIG. 10e shows aspects of a sensing tip of a guidewire 1026 inaccordance with the present disclosure. The guidewire 1026 includes amicrobasket electrode array 1027 including an array of microfingers1029, each arranged in a bowed shape so as to extend out from the axisof the lumen into which the device is placed. Aspects of a singlemicrofinger 1029 in the array is shown in the detailed view A. Themicrofinger 1029 includes one or more sensors or electrodes 1028, eachin accordance with the present disclosure. In the example shown in FIG.10e , the electrode 1028 is shown patterned so as to face radiallyoutwards from the center of the lumen into which the sensing tip isdeployed. The electrode 1028 may be formed in accordance with thepresent disclosure. One or more regions of the microfinger 1029 may beisolated from the surroundings with an insulating layer (e.g., apassivated layer, a dielectric layer, a polymer, PTFE, parylene, etc.).In aspects, the microfinger 1029 may be configured so as to deploy toreach the shape shown in FIG. 10e during a predetermined procedure(e.g., actuation, sheath retraction, core extension, biodegradation of arestraint, etc.). In aspects, the microbasket array 1027 may be deployedduring use so as to interface with the walls of a lumen, in accordancewith the present disclosure. One or more microfingers 1029 and/orsensors or electrodes 1028 may be coupled with a connector or acontroller 1030, preamp, microcircuit, circuit, a connector, or the likeeach in accordance with the present disclosure.

FIG. 10f illustrates aspects of a sensing tip of a sensing guidewire1031 in accordance with the present disclosure. The guidewire generallyincludes one or more lumens and a microporous tip 1032 which includesone or more ports 1038 through which one or more protruding microneedleelements 1034 may pass upon deployment. The guidewire 1031 is shown in aretracted state 1036 which may be suitable for accessing a targetanatomical site in accordance with the present disclosure, as well as ina deployed state 1037 which is suitable for interfacing one or moresensors or electrodes with the target anatomical site as part of aprocedure. One or more of the protruding microneedle elements 1034 mayinclude a sensor or an electrode on the exposed tip 1033 thereof. One ormore of the microneedle elements 1034 may include one or more features1035 such as bumps, step changes in insulation, etc. configured so as tolimit the penetration depth of such exposed tips 1033 into the adjacenttissues. One or more aspects of the guidewire 1031 or aspects of theexposed tips 1033 may be coupled to a controller 1039, preamp,microcircuit, circuit, a connector, or the like each in accordance withthe present disclosure.

FIG. 10g shows aspects of a sensing tip of a sensing guidewire 1041 inaccordance with the present disclosure. The sensing guidewire 1041includes a plurality of deployable tines 1042, each tine 1042 includingone or more sensors and/or electrodes each in accordance with thepresent disclosure. The deployable tines 1042 may be held togetherduring storage and delivery to a surgical site of interest by arestraint mechanism 1043 (such as a biodegradable adhesive, a watersoluble matrix, a thermally stabilized shape set, etc.). Upon deliveryto the anatomical site, upon contact with a fluid, etc. the restraintmechanism 1043 may release the tines 1042 to as to deploy 1044 them toform a deployed state. In the deployed state, the tines 1042 may besignificantly biased 1047 towards the walls of a lumen into which thesensing tip has been placed, etc. One or more aspects of the guidewire1041 or aspects of the tines 1042 may be coupled to a controller 1046,preamp, microcircuit, circuit, a connector, or the like each inaccordance with the present disclosure.

FIG. 10h shows aspects of a sensing tip of a sensing guidewire 1051 inaccordance with the present disclosure. The sensing tip includes one ormore microfingers 1052 in accordance with the present disclosure. Themicrofingers 1052 shown in FIG. 10h are equipped with a plurality ofsensing points 1053, each including a sensor or electrode in accordancewith the present disclosure. The sensing guidewire 1051 is shown placedwithin a lumen 25 within a body and the microfingers 1052 have beendeployed such that the sensing points 1053 may interface with the wallsof the lumen 25. One or more of the sensing points 1053 may be coupledwith a controller 1054, preamp, microcircuit, circuit, a connector, orthe like each in accordance with the present disclosure in order torecord signals therefrom during a monitoring session. In aspects, thesensing guidewire 1051 may be retracted while in the position shown soas to drag 1055 the sensing points 1053 along the walls of the lumen 25,so as to map the physiologic signals there upon. In aspects, such aconfiguration may be advantageous for mapping electrophysiologicalinformation along the lumen wall, for generating an anatomical map, forevaluating the location of active neuromuscular sites, evaluating thetype and/or direction of neurological traffic in the vicinity of eachsensing point 1053, etc.

FIG. 10i illustrates aspects of a sensing tip of a sensing guidewire1060 in accordance with the present disclosure. The sensing tip includesa jacket 1062 and a shaped tip 1064, the jacket 1062 dimensioned with adiameter 1070 sufficiently small so as to access an anatomical site ofinterest within a body. The sensing tip further includes one or moresensors 1066 each nested into an access port. The guidewire 1060 alsoincludes one or more lead wires 1068 interconnected with the sensors1066 and the proximal end of the guidewire 1060 (e.g., a connector, amicrocircuit, a controller 1072, a preamp, microcircuit, circuit, aconnector, etc.).

In aspects, one or more of the sensors may be configured to monitor alocal analyte concentration (e.g., a hormone concentration,norepinephrine, catecholamine, renin, angiotensin II, an ionconcentration, a water level, an oxygen level, etc.), a pH level, etc.

FIG. 10j illustrates aspects of a delivery catheter 1069 in accordancewith the present disclosure. The delivery catheter 1069 may provide asheath through which one or more additional elements may be guided 1072to an anatomical site within the body and/or to interconnect a distalportion thereof with a controller 1070, preamp, microcircuit, circuit, aconnector, or the like. The delivery catheter 1069 may include one ormore electrodes 1071 configured for purposes of sensing, stimulation,stress test analysis, neuromodulation, surgical procedural outcome,changes in traffic associated therewith, as reference electrodes, or thelike. In aspects, the delivery catheter 1069 may include a bulbousfeature 1073 sized and dimensioned so as to provide a stop gap forentrance into a target lumen, for providing hemostasis within a targetlumen, etc.

FIG. 10k illustrates aspects of a delivery catheter 1075 with a hollowlumen configured along the length thereof, including one or more sensors1077, a bulbous feature 1078 each in accordance with the presentdisclosure. The delivery catheter 1075 is shown with an associatedguidewire 1079, deployed from the tip thereof. The guidewire 1079includes one or more zones 1080, 1082 each in accordance with thepresent disclosure. The guidewire 1079 includes a sensing tip 1080attached to a soft guiding tip 1081 configured so as to measure one ormore physiologic aspects of an adjacent tissue when positioned within alumen of a body. The guidewire 1079 includes a biasing zone 1082including one or more electrodes and/or sensors, each in accordance withthe present disclosure. In aspects, the biasing zone 1082 may beconfigured to deploy upon protrusion of the guidewire 1079 tip beyondthe delivery catheter 1075, upon retraction of the delivery catheter1075, upon actuation of an element within the biasing zone 1082, uponadjustment of a repositionable core within the guidewire 1079, or thelike. The guidewire 1079 may be configured so as to advance 1083 orretreat 1084 along the length of a lumen into which it is placed duringa procedure.

In aspects, the guidewire 1079 may include a repositionable core inorder to construct a sensing guidewire 1079 with a deployable tipstructure (e.g., with a deployable tip array, a basket arrangement,helical biasing zone 1082, etc.).

In aspects, one or more sensors and/or electrodes (i.e., included within1082, 1080) on the guidewire 1079 may be configured to communicate withone or more sensors and/or electrodes 1077 on the delivery catheter1075.

FIG. 10l illustrates aspects of a guidewire 1101 in accordance with thepresent disclosure coupled with a lumen wall 25 into which it has beendeployed (i.e., as part of a procedure). The guidewire 1101 may becoupled with a controller 1103 in accordance with the presentdisclosure. The guidewire 1101 may include one or more sensing tips 1105for interfacing with the lumen wall 25. The guidewire 1101 may include asoft tip 1107 for assisting with delivery of the guidewire 1101 into thelumen. In aspects, the guidewire 1101 may include one or more electrodes1109 positioned near to the distal tip of the guidewire 1101 within abiasing zone 1111 in accordance with the present disclosure. The biasingzone 1111 includes a helically shaped region (i.e., such as formed in ashape setting procedure, etc.), so as to bias the electrodes 1109against the lumen wall 25 upon deployment.

In aspects, the guidewire 1101 may be configured with a characteristicdiameter d, of less than 1.5 mm, less than 1 mm, less than 0.75 mm, lessthan 0.5 mm, less than 0.25 mm, or the like. The shape set aspects ofthe biased zone 1111 may be configured so as to transition from adisconnected region along the lumen wall 25 into a zone of contact, soas to provide consistent contact with the lumen wall 25 during aprocedure. In aspects, the guidewire 1101 may be configured so as totransition from a substantially elongate shape to a deployed shape(e.g., a helical electrode arrangement, etc.), upon deployment into thelumen of a vessel within a body.

In aspects, the guidewire 1101 may be configured for placement within avessel, for delivery to or within the parenchyma of an organ into whichthe vessel extends, or the like as part of a surgical procedure. Inaspects, the guidewire 1101 may be configured for nerve monitoring,electrophysiological monitoring, stimulation, and/or ablation proceduresin accordance with the present disclosure. In aspects, the guidewire1101 may be configured to provide a path, over which a second surgicaltool may be delivered to the vessel, the guidewire sensing tip 1105configured to monitor one or more physiologic functions relevant to theoperation and/or evaluation of a procedure performed by the surgicaltool. In aspects, one or more of the zones 1105, 1111, etc. may beconfigured for sensing local electrophysiological activity, stimulatinglocal neural anatomy, delivering a substance to local tissues, and/orneuromodulating local neural anatomy (e.g., ablating, denervating, etc.)in accordance with the present disclosure. In aspects, a guidewire inaccordance with the present disclosure may include a sensing zone 1105located at the distal tip thereof, an ablating/stimulating zone 1111located along the length of the guidewire proximally to the distal tip,and a second sensing zone 932, as shown in FIG. 9d , located along thelength of the guidewire proximally to the ablating/stimulating zone (notexplicitly shown). In aspects, functions performed within each zone 912,914, 932 of FIG. 9d , 1105, 1111 of FIG. 10l , etc. during a proceduremay be coordinated by a controller in accordance with the presentdisclosure for purposes of diagnosis, determining the extent of aprocedure, performing a neuromodulation procedure, denervating a neuralstructure, combinations thereof, or the like.

In aspects, the guidewire 1101 may be configured with a shape set region1111, configured to bias 1113 one or more regions 1111 of the guidewireagainst a wall of a lumen 25 into which it has been placed. In aspects,the guidewire 1101 may include a wire basket, a helical region, aballoon, etc. in order to provide such bias 1113 against an adjacentlumen wall 25. In aspects, the shape set region 1111 may be retractablycollapsible into a delivery sheath (i.e., a sheath provided over theguidewire sized and dimensioned for delivery thereof to an anatomicalsite of interest). In aspects, the shape set region 1111 may be deployedso as to bias against a wall of a lumen 25 into which it is placed by anactuation procedure, retraction of a delivery sheath, protrusion of theguidewire distal tip beyond the distal tip of a delivery sheath, etc.

In aspects, the biasing region 1111 may be deployed via actuation of anactuator element embedded therein. In aspects, such an actuator elementmay include an active material transducer in accordance with the presentdisclosure. In aspects, the actuation may be provided by a shape setshape memory alloy, such as may be introduced into the lumen at atemperature substantially below a threshold transition temperature, andundergo a deployment so as to bias against the lumen wall 25 uponincreasing temperature to substantially above the threshold transitiontemperature (e.g., such as via natural heating from adjacent tissuestructures, via active heating, via current flow associated with astimulation and/or ablation procedure, etc.). In aspects, suchdeployment may be achieved by other forms of actuation such as but notlimited to electroactive material expansion, retraction of a centralcore, pulling of a tendon core, retraction of a sheath, dissolution of aconstraining element, etc.

In aspects, a guidewire in accordance with the present disclosure mayinclude a bulbous feature located within the vicinity of the distal tipthereof. The bulbous feature may be configured to bottom out theguidewire within a lumen (e.g., when the lumen diameter approaches thatof the bulbous feature, between a step between a feeding lumen and atreatment lumen, etc.) as it is advanced there along during a placementprocedure. Such a feature may be advantageous to position the distal tipof the guidewire within a treatment lumen (e.g., a vessel, an artery, avein, a tubule, etc.), to provide hemostasis to the treatment lumen,etc.

FIG. 10m illustrates aspects of a guidewire 1115 in accordance with thepresent disclosure. The guidewire 1115 may be coupled with a controller1125 in accordance with the present disclosure. The guidewire 1115 mayinclude one or more sensing tips 1117 for interfacing with a localanatomical site during a procedure. The guidewire 1115 may include asoft tip 1117 for assisting with delivery of the guidewire 1115 into alumen within a body. In aspects, the guidewire 1115 may include one ormore electrodes 1119 positioned near to the distal tip of the guidewire1115 within a biasing zone 1118 in accordance with the presentdisclosure. The biasing zone 1118 shown in FIG. 10m includes a helicallyshaped region (e.g., such as formed in a shape setting procedure, etc.),so as to bias the electrodes 1119 against an adjacent wall during aprocedure. In the biasing zone 1118 may take a deployed form 1120 duringplacement, or as part of a placement procedure. In aspects, the deployedform 1120 may take on a bulbous shape, an expanded region with taperedends, a cylindrical profile, or the like.

In aspects, the biasing zone 1118 may include a shape set aspect,configured so as to transition from a first shape that is notsufficiently biased so as to contact an adjacent lumen wall, to a regionover which the biasing is sufficient to provide consistent contact withan adjacent lumen wall during a procedure. In aspects, the biasing zone1118 of the guidewire 1115 may be configured so as to transition from asubstantially elongated shape to a deployed shape (e.g., a helicalelectrode arrangement, etc.), upon deployment into the lumen of a vesselwithin a body.

In aspects, the guidewire 1115 may be configured with one or morediameters along the length thereof. In aspects, a distal characteristicdiameter d₁, for the guidewire 1115 may be arranged such that d₁ is lessthan 1.5 mm, less than 1 mm, less than 0.75 mm, less than 0.5 mm, lessthan 0.25 mm, or the like. In aspects, a proximal characteristicdiameter d₂ may be arranged such that d₂ is less than 1.0 mm, less than0.75 mm, less than 0.5 mm, less than 0.025 mm, or the like. In aspects,the proximal diameter d₂ may be sized so as to provide a sufficientlyminiature profile over which an additional catheter and/or surgical toolmay be deployed within the body. In aspects, the distal characteristicdiameter d₁ may be configured so as to accommodate an embeddedmicrocircuit 1123 and/or interconnections thereto.

In aspects, a guidewire 1115 in accordance with the present disclosuremay include a microelectronic circuit 1123 embedded within or coupled tothe distal tip 1117 thereof, as well as coupled to an interconnectand/or controller 1125 coupled to the proximal end thereof, configuredto control signal flow to/from one or more zones 1118, 1117, etc. of theguidewire 1115 for purposes of performing a procedure in accordance withthe present disclosure.

In aspects, a guidewire in accordance with the present disclosure mayinclude one or more electrodes, each electrode configured to sense,stimulate, and/or ablate a local anatomical site within a body. Inaspects, the guidewire may include a plurality of ablation electrodesconfigured to interface with a wall of a lumen into which the guidewireis placed, so as to provide coupling for delivery of radiofrequency,and/or microwave frequency energy into the wall of the lumen and/ortissues surrounding the lumen, as part of a procedure in accordance withthe present disclosure. In aspects, the guidewire may be configured tomonitor one or more physiologic aspects in conjunction with the energydelivery process (e.g., before, during, after, etc.).

In aspects, a system in accordance with the present disclosure mayinclude a delivery catheter including one or more electrodes, and aguidewire including one or more electrodes, the system configured topass energy between the catheter electrode(s) and the guidewireelectrode(s) as part of a procedure. In aspects, the system may beconfigured to monitor electrophysiological activity between theguidewire electrode(s) and the catheter electrode(s) as part of aprocedure.

In aspects, a guidewire in accordance with the present disclosure mayinclude a drug eluting region (e.g., over an electrode, at the distaltip, etc.), configured so as to elute a drug into the vicinity of theregion during a procedure (e.g., so as to minimize clotting, minimizedamage to adjacent structures, etc.).

In aspects, a guidewire in accordance with the present disclosure mayinclude a thrombus net coupled to the distal tip thereof. The thrombusnet may be configured so as to bridge a cross section of a lumen intowhich the guidewire is placed during a procedure. The thrombus net maybe configured to capture debris generated at a site along the system,guidewire, associated catheter, etc. during a procedure in accordancewith the present disclosure. The thrombus net may be configured so as towithdraw any captured debris along with the guidewire during withdrawalfrom the body.

FIG. 10n illustrates aspects of a guidewire 1150 in accordance with thepresent disclosure placed within a lumen 25. The guidewire 1150 mayinclude one or more zones 1154, 1152 in accordance with the presentdisclosure. The guidewire 1150 includes a sensing zone 1154 locatedalong the length thereof for interfacing with the lumen wall proximallyto a treatment site. The guidewire 1150 includes a sensing tip 1152located at the distal tip thereof for interfacing with the lumendistally to a treatment site. The guidewire 1150 includes one or moremicroneedles 1156, which may be advanced from the body of the guidewire1150 into the wall of the lumen 25 into which it has been placed as partof a procedure. Such needle advancement or retraction 1158 may becoordinated by an operator, a controller 1162, etc. In aspects, themicroneedles 1156 may provide a means for delivering a chemical agent1160 into the tissues surrounding the lumen 25. In aspects, themicroneedles 1156 may include one or more electrodes to monitor and/orinterface (e.g., stimulate, ablate, etc.) the local tissues upondeployment therein. In aspects, the guidewire 1150 may be configured soas to deliver the microneedles 1156 into the adventitia of the lumen 25,or optionally directly into the parenchyma of an organ to be treated.Such a configuration may be advantageous to provide a mild inflammatoryagent, a neurolytic agent, a neurotoxin, a cancer treating agent, aneuroblocking agent, a neurostimulating agent, etc. into the targettissues as part of a treatment procedure in accordance with the presentdisclosure.

The methods, devices, and systems disclosed in the present disclosurewill be better understood by reference to the following examples whichare offered by way of illustration and which one of skill in the artwill recognize are not meant to be limiting.

EXAMPLES Example 1

The following non-limiting example is directed at the treatment ofneurogenic pathways for tumor growth and metastasis of pancreatic ductaladenocarcinoma (PDAC). A control experiment was performed with 10athymic nude mice. The 10 mice were surgically prepared underanesthesia, and the surgical site was cleaned with 75% ethanol solution.A dorsal incision was used to access the spleen, pancreas and associatedarterial supply. Mia PaCa2 human pancreatic cancer cells were seededinto the pancreas of each mouse. In 5 of the mice, the celiac ganglionand surrounding nerves were ablated with ethanol. The surgicalprocedures were completed and the mice were returned to Plexiglass boxesfor observation.

The animals were monitored for detectable sickness related behavior andtumor growth was monitored via in vivo bioluminescent imaging techniques(IVIS® imaging system). Animals were monitored for relative changes inthe following criteria: detectable sickness-related behavior, hunchingand postural changes, signs of tumor growth in the animals' back(visible lumps), increases in piloerection, changes in skin tone andcharacter, and changes in voluntary movement levels and exploratorybehavior. At 2 weeks post-surgery, the experimental mice demonstratedimproved skin tone and movement versus the control mice. At 3 weeks,IVIS® imaging of the mice showed that the average tumor size in theexperimental group was 55% the average tumor size in the control group(based upon in vivo luciferase subject ROI imaging of the mice). As thetumor growth continues the experimental group may continue to exhibitslowed growth of the pancreatic ductal adenocarcinoma, reduced painlevels, and reduced perineural invasion of the PDAC cells intosurrounding parasympathetic nerves, and the like.

Example 2

The following, non-limiting example, is directed to the identification,evaluation, and subsequent treatment of nerves in a subject. Relating tothe alteration of pancreatic neuroendocrine or sensory function, acatheter in accordance with the present disclosure may be advanced alongan arterial pathway to the superior and inferior pancreaticoduodenalarteries and branches thereof, the dorsal pancreatic artery, and thesplenic artery. The catheter tip, equipped with one or more sensingelements, each in accordance with the present disclosure, is advancedinto each of the arteries in sequence. Once placed within acorresponding artery, baseline readings of neural traffic are takenaround the wall of the artery. Nerve traffic may be characterized as“normal”, “abnormal”, “hyperactive”, “underactive”, etc. according topopulation acquired data, previously acquired data, etc. The nerve typesnearest to each of the sensors may be identified directly from thebaseline traffic as being somatosensory, sympathetic, parasympathetic innature, or the like. Such identification may be made based upon thecharacter of the signals, the temporal changes in the signals withbreathing, heart rate, or reflex response to a stimulus, the directionof neural traffic (afferent or efferent) along the artery wall, theaction potential characteristics of the signals, etc. If identificationor traffic characterization cannot be completed based upon the baselinerecordings, a stress test may be performed on the pancreas, anassociated organ, coupled neuroendocrine circuit, or the subject on thewhole in accordance with the present disclosure.

In one non-limiting example of a neuro-specific stress test, a bolus ofa somatosensory neuro agonist (e.g., low dose capsaicin) is injectedinto the artery and the neural traffic is monitored during theassociated stress response. The monitored changes in neural trafficassociated with the capsaicin stress test may be associated withsomatosensory receptor activity in the region of the pancreas served bythe associated artery.

Relating to the modulation of insulin production related neuroendocrinecircuit, the neural traffic may be monitored in the associated arteryduring an associated stress test. In such a stress test, a bolus ofglucose may be administered to the subject, and neural traffic may bemonitored during the responding insulin regulating reflex reaction. Suchchanges in neural traffic may be used to identify neural pathwaysassociated with the insulin regulating neuroendocrine circuit in thesubject, as well as identify the location of those nerves with respectto the positioning of one or more of the sensors on the cathetersituated in the associated artery.

Relating to the alteration of pancreatic juice secretion in thepancreas, the neural traffic may be monitored in the associated arteryduring a sympathetic nervous system or parasympathetic altering stresstest (e.g., via administration of a sympathetic/parasympatheticagonist/antagonist, vagal stimulation, breath hold, tilt test, etc.).Such neural traffic may be used to identify the vagal nerves and thelocation of the vagal nerves with respect to the positioning of one ormore of the sensors on the catheter situated in the associated artery.Vagal nerve traffic to the pancreas influences the production,secretion, and composition of the pancreatic juices. In the lead-up to apancreas resection surgery (e.g., so as to remove a pancreatic tumor),the vagal nerve pathway may be modulated or remodeled as describedherein to reduce the amount or alter the composition of the pancreaticjuices.

Upon identification of the nerve types and traffic characteristics, adecision may be made as to whether or not to treat, pace, modulate,ablate, etc. the nerves (e.g., selectively, collectively, etc.). If thedecision is made to treat the nerves, one or more nerve treatingelements in the catheter (e.g., energy or chemical delivery elements, RFablation elements, neuroselective ablative agent delivery, generalneural ablative agent delivery, placement of a neuromodulatinginterface, etc.) may be activated so as to complete the treatmentprocedure. Upon completion, the catheter may be moved to one or more ofthe other arteries, removed from the body of the subject, etc.

Example 3

The following, non-limiting example, is directed to treatment ofpancreatic cancer in a human subject. A catheter in accordance with thepresent disclosure may be advanced along an arterial pathway to thesuperior and inferior pancreaticoduodenal arteries and branches thereof,the dorsal pancreatic artery, and the splenic artery. The catheter tip,equipped with one or more sensing elements, each in accordance with thepresent disclosure, is advanced into each of the arteries in sequence.Once placed within a corresponding artery, baseline readings of neuraltraffic are taken around the wall of the artery. Once the presence,nerve types, function, and/or local neural activity levels areconfirmed, an ablation procedure may be completed with the catheter toperform one or more of the following functions: 1. disconnect and/orblock the central nervous system (CNS) from the sympathetic receptors inthe pancreas; 2. disconnect pain sensory receptors in the pancreasand/or surrounding organs from the CNS; and 3. disconnect and/or blockthe CNS from the parasympathetic receptors in the pancreas. Withoutbeing limited to one given theory, the ablation of the different nervetypes contribute to the following roles in hindering the cancerprogression and/or improving patient outcomes: 1. decreasingsympathetically mediated neurotransmitter release in the pancreas,decreases tumor growth rates; 2. disconnection of afferent nervesreduces pain associated with tumor growth; and 3. disconnection of vagalnerves down regulated parasympathetically mediated neurotransmitterrelease in the pancreas, altering pancreatic juice composition andsecretion. Furthermore, physically blocking the neural pathways (e.g.,such as with post procedural scar tissue, via disruption of the nervechannels through the tissues, etc.), may physically hinder themetastatic progression of the cancer along those channels and out intosurrounding tissues.

In the associated or subsequent arteries, upon placement of the cathetertip in the vicinity of the target nerves, the catheter may be used totreat the nerves in accordance with the present disclosure. Sensors onthe catheter tip may be used to confirm completion of the procedure andthen the catheter may be advanced to another associated artery, orremoved from the subject.

The procedure may be used to decrease growth rate of the canceroustumor, decrease cancer related pain, alter pancreatic juice formation,composition, and/or secretion rate, decrease neural signaling in thevicinity of the microenvironment of the tumor, and/or block offmetastatic pathways for the cancer cells.

Example 4

The following, non-limiting example, is directed to treatment ofpancreatic cancer in a human subject. A catheter in accordance with thepresent disclosure may be advanced along an arterial pathway to thesuperior and inferior pancreaticoduodenal arteries and branches thereof,the dorsal pancreatic artery, and the splenic artery. The catheter tipmay be equipped with one or more electrode elements and/or drug deliveryelements for treating target nerves in the vicinity of the associatedartery.

Upon placement in the vicinity of the target nerves, the catheter may beused to treat the nerves in accordance with the present disclosure. Uponcompletion of the procedure, the catheter may be advanced to anotherassociated artery, or removed from the subject.

The procedure may be used to decrease growth rate of the canceroustumor, decrease cancer related pain, alter pancreatic juice formation,composition, and/or secretion rate, and/or block off metastatic pathwaysfor the cancer cells.

Example 5

The following, non-limiting example, is directed to treatment of femurbone cancer in a human subject. A catheter in accordance with thepresent disclosure may be advanced along an arterial pathway to anutrient artery and or a branch thereof serving the femur bone so as tointerface with and/or to treat nerves innervating a spongy bone, aperiosteal space, a joint, an epiphyseal space, a metaphyseal space, orthe like. The catheter tip, equipped with one or more sensing elements,each in accordance with the present disclosure is positioned within thenutrient artery such that the sensing elements are coupled to the localnerves surrounding the artery. Once placed within a correspondingartery, baseline readings of neural traffic are taken around the wall ofthe artery. The nerve types, presence, and/or function are confirmed andan ablation procedure, stimulation procedure, or selectiveneuro-remodeling procedure is completed with the catheter to perform oneor more of the following functions: 1. disconnect and/or block the CNSfrom the sympathetic receptors in the bone; 2. disconnect pain sensoryreceptors in the bone and/or surrounding organs from the CNS; and 3.disconnect the parasympathetic receptors in the bone from the CNS.Without being limited to one given theory, the ablation of the differentnerve types contribute to the following roles in hindering the cancerprogression and/or improving patient outcomes: 1. decreasingsympathetically mediated neurotransmitter release in the bone, decreasestumor growth rates, increases bone growth and decreases bone resorption;2. disconnection of afferent nerves reduces pain associated with tumorgrowth in the bone; and 3. blocking of parasympathetic nerves cuts offmetastatic pathways for the tumor cells to migrate into differentregions of the body. One or more of the procedures may be completeddepending on the goal of the procedure. Physically blocking the neuralpathways (e.g., such as with post procedural scar tissue, via disruptionof the nerve channels through the tissues, etc.), may physically hinderthe metastatic progression of the cancer along those channels and outinto surrounding tissues.

Upon placement in the vicinity of the target nerves, the catheter may beused to treat the nerves in accordance with the present disclosure.Sensors on the catheter tip may be used to confirm completion of theprocedure and then the catheter may be advanced to another associatedartery, or removed from the subject.

The procedure may be used to decrease growth rate of the canceroustumor, decrease cancer related pain, alter bone growth and resorptionrates, and/or block off metastatic pathways for the cancer cells toescape into surrounding tissues.

Example 6

The following, non-limiting example, is directed to treatment of femurcancer and/or associated cancer pain in a human subject. A catheter inaccordance with the present disclosure may be advanced along an arterialpathway to a nutrient artery and or a branch thereof serving the femurbone. The catheter tip may be equipped with one or more electrodeelements and/or drug delivery elements for treating nerves in thevicinity of the associated artery.

Upon placement in the vicinity of the target nerves, the catheter may beused to treat the nerves in accordance with the present disclosure. Uponcompletion of the procedure, the catheter may be advanced to anotherassociated artery, or removed from the subject.

The procedure may be used to decrease growth rate of the canceroustumor, decrease cancer related pain, alter bone growth and resorptionrates, and/or block off metastatic pathways for the cancer cells.

Example 7

The following, non-limiting example, is directed to bone reinforcementto treat and/or prevent development of osteoporosis in a human subject.A catheter in accordance with the present disclosure may be advancedalong an arterial pathway to a nutrient artery and or a branch thereofserving the femur bone. The catheter tip, equipped with one or moresensing elements, each in accordance with the present disclosure, ispositioned within the nutrient artery such that the sensing elements arecoupled to the local nerves surrounding the artery. Once placed within acorresponding artery, baseline readings of neural traffic are takenaround the wall of the artery. The nerve types, presence, and/orfunction are confirmed and an ablation procedure, stimulation procedure,or selective neuro-modulation procedure is completed with the catheter,or alternatively using the catheter to guide placement of aneuromodulation electrode, etc. to perform one or more of the followingfunctions: 1. disconnect and/or block the CNS from the sympatheticreceptors in the bone (e.g., down regulate local sympathetic nerveactivity); 2. disconnect pain sensory receptors in the bone and/orsurrounding organs from the CNS; and 3. stimulate the parasympatheticreceptors in the bone (e.g., up regulate local parasympathetic nerveactivity). Without being limited to one given theory, the ablationand/or stimulation of the different nerve types contribute to thefollowing roles in altering the bone density in the femur,slowing/reversing the progression of osteoporosis in the subject, and/orimproving patient outcomes: 1. decreasing sympathetically mediatedneurotransmitter release in the bone, increases bone growth anddecreases bone resorption rates; 2. disconnection of afferent nervesreduces pain associated with bone remodeling processes in the femurbone; and 3. stimulation or increases in activity associated withparasympathetic nerves up regulates parasympathetically mediatedneurotransmitter release in the bone, increasing bone growth anddecreasing bone resorption. One or more of the procedures outlined abovemay be completed depending on the goal of the procedure. Physicallyblocking the neural pathways (e.g., such as with post procedural scartissue, via disruption of the nerve channels through the tissues, etc.),may physically hinder the re-innervation of the nerves along thosechannels, thus slowing the re-innervation process and improving thedurability of the procedure.

Example 8

The following, non-limiting example, is directed to bone reinforcementto treat and/or prevent development of osteoporosis in a human subjector to the treatment of bone cancer in a human subject. A focused energyor chemical delivery element is guided to the nutrient artery of thetarget bone (e.g., femur bone). In one, non-limiting example, the energydelivery is provided by a focused high frequency ultrasound (HIFU)delivery system. The focused energy is delivered to the regionsurrounding the nutrient artery and/or the perivascular region of thebone. A thermal increase in the target tissues is used to ablate thenerves within the target tissues. In another, non-limiting example, asympathetic nerve selective neurotoxin (e.g., 6-hydroxydopamine,ω-conotoxin GVIA, bungarotoxin, etc.), or generally acting neurotoxin(e.g., ethanol, phenol, etc.), is directed to the tissues surroundingthe nutrient artery or perivascular space of the target bone (e.g., afemur). Such delivery of energy or chemical may be guided by one or moreimaging techniques (e.g., ultrasound, CT, MRI, etc.). The energy orchemical delivery is used to perform one or more of the followingfunctions: 1. disconnect and/or block the CNS from the sympatheticreceptors in the bone (e.g., down regulate local sympathetic nerveactivity); 2. disconnect pain sensory receptors in the bone and/orsurrounding organs from the CNS; and 3. preserve parasympatheticinnervation in the bone (e.g., such as via application of aneuro-selective toxin). Without being limited to one given theory, theablation and/or selective preservation of the different nerve typescontribute to the following roles in altering the bone density in thefemur, slowing/reversing the progression of osteoporosis in the subject,and/or improving patient outcomes: 1. decreasing sympatheticallymediated neurotransmitter release in the bone, increases bone growth anddecreases bone resorption rates; 2. disconnection of afferent nervesreduces pain associated with bone remodeling processes in the femurbone; and 3. maintains levels of activity associated withparasympathetic nerves up regulates parasympathetically mediatedneurotransmitter release in the bone, increasing bone growth anddecreasing bone resorption. One or more of the procedures outlined abovemay be completed depending on the goal of the procedure. Physicallyblocking the neural pathways (e.g., such as with post procedural scartissue, via disruption of the nerve channels through the tissues, etc.),may physically hinder the re-innervation of the nerves along thosechannels, thus slowing the re-innervation process and improving thedurability of the procedure.

Example 9

The following, non-limiting example, is directed to treatment ofprostate cancer or benign prostate hyperplasia in a human subject. Acatheter in accordance with the present disclosure may be advanced alongan arterial pathway to a prostatic artery and or a branch thereofserving the prostate. The catheter tip, equipped with one or moresensing elements, each in accordance with the present disclosure ispositioned within the prostatic artery such that the sensing elementsare coupled to the local nerves surrounding the artery. Once placedwithin a corresponding artery, baseline readings of neural traffic aretaken around the wall of the artery. The nerve types, presence, and/orfunction are confirmed and an ablation procedure, stimulation procedure,or selective neuro-remodeling procedure is completed with the catheterto perform one or more of the following functions: 1. disconnect and/orblock the CNS from the sympathetic receptors in the prostate; 2.disconnect pain sensory receptors in the prostate and/or surroundingorgans from the CNS; and 3. disconnect the parasympathetic receptors inthe prostate from the CNS. Without being limited to one given theory,the ablation of the different nerve types contribute to the followingroles in hindering the cancer progression and/or improving patientoutcomes: 1. decreasing sympathetically mediated neurotransmitterrelease in the prostate decreases tumor growth rates and slows orreverses prostate hyperplasia; 2. disconnection of afferent nervesreduces pain associated with tumor growth in the prostate; and 3.blocking of parasympathetic nerves cuts off metastatic pathways for thetumor cells to migrate into different regions of the body. One or moreof the procedures may be completed depending on the goal of theprocedure. Physically blocking the neural pathways (e.g., such as withpost procedural scar tissue, via disruption of the nerve channelsthrough the tissues, etc.), may physically hinder the metastaticprogression of the cancer along those channels and out into surroundingtissues.

The baseline readings or readings made during one or more stress testsin accordance with the present disclosure, may be used to ensure thattreatment is targeting the correct nerves, and not prone to causingcollateral damage to surrounding structures. In one non-limitingexample, a local electrical stimulus is provided to the surroundingnerves via the catheter tip (e.g., via a collection of the sensingelements, via dedicated stimulation/ablation electrodes, etc.) as partof an identification, or functional assessment step of the procedure.During stimulation, hemodynamics and/or feelings of subject sensation inthe penis are determined, if penile sensation or response is detected,the catheter may be advanced to a new site, an alternative branch of theprostatic artery, so as to ensure that the treatment does specificallytargets nerves coupled to the prostate or a cancerous tumor associatedtherewith.

Upon placement in the vicinity of the target nerves, the catheter may beused to treat the nerves in accordance with the present disclosure.Sensors on the catheter tip may be used to confirm completion of theprocedure and then the catheter may be advanced to another associatedartery, or removed from the subject.

The procedure may be used to decrease growth rate of the canceroustumor, decrease cancer related pain, alter prostate growth rates, slow,halt, or reverse prostate hyperplasia, and/or block off metastaticpathways for the cancer cells to escape into surrounding tissues.

Example 10

The following, non-limiting example, is directed to a method for using asystem in accordance with the present disclosure to identify and assessthe functionality of one or more nerves in the vicinity of an arteryserving a target organ in a human subject. A catheter in accordance withthe present disclosure may be advanced along an arterial pathway to theartery or a branch thereof serving the target organ. The catheter tip,equipped with one or more sensing elements, each in accordance with thepresent disclosure is positioned within the artery such that the sensingelements are coupled to the local nerves surrounding the artery. Onceplaced within a corresponding artery, baseline readings of neuraltraffic are taken around the wall of the artery. The nerve types,presence, and/or function are confirmed during baseline testing orduring application of a stress test in accordance with the presentdisclosure. In one non-limiting example of such a stress test, one ormore boluses of a neurotransmitter, hormone, a medication, or the likeis released into the artery from the sensing tip of the catheter. Thecorresponding neural traffic is recorded during the stress test and theidentity, location, functionality, sensitivity of the neural traffic tothe bolus, or the like is analyzed to select one or more targets fortreatment, to assess the subject for a treatment option, etc. Dependingon the results of the analysis, an ablation procedure, stimulationprocedure, or selective neuro-remodeling procedure may be completed withthe catheter in accordance with the present disclosure, or the catheteris moved to an alternative test site, or removed from the subject. Sucha configuration may be advantageous for assessing organ, neuroendocrine,function or sensitivity to one or more aspects of the stress test, toidentify nerves in the vicinity of the catheter for possible treatmentthereof, etc.

After identification of the target nerves, a procedure may bepreferentially directed at the target nerves while minimizing collateraldamage or unwanted effects associated with treating the wrong nervestructures. In one non-limiting example, the stress test may be used toidentify the regions with high levels of sympathetic nerves and theregions with high levels of parasympathetic nerves. Depending on thegoal of the therapy (e.g., sympathectomy while preserving theparasympathetic innervation, etc.), the therapy may be directed towardsthe target nerves.

Example 11

The following, non-limiting example, is directed to a method for using asystem in accordance with the present disclosure to treat one or moretarget nerves in the vicinity of an artery serving a target organ in ahuman subject. A catheter in accordance with the present disclosure maybe advanced along an arterial pathway to the artery or a branch thereofserving the target organ. The catheter tip, equipped with one or moresensing elements and therapeutic elements, each in accordance with thepresent disclosure is positioned within the artery such that the sensingelements are coupled to the local nerves surrounding the artery. Onceplaced within a corresponding artery, baseline readings of neuraltraffic are taken around the wall of the artery. The nerve types,presence, and/or function are confirmed during baseline testing orduring application of a stress test in accordance with the presentdisclosure. Depending on the results of the analysis, an ablationprocedure, stimulation procedure, or selective neuro-remodelingprocedure may be completed with the catheter in accordance with thepresent disclosure, or the catheter may be moved to an alternative testsite, or removed from the subject. The sensing elements may beconfigured to monitor the associated neural traffic before, during,and/or after the procedure so as to assess when the procedure has beencompleted (e.g., when a target nerve has been functionally disabled,when a non-target nerve is starting to be affected by the therapy,etc.). Such a configuration may be advantageous for performing suchprocedures with a high degree of confidence related to the completionthereof, and to the minimizing of collateral damage associatedtherewith.

Example 12

The following, non-limiting example, is directed to a method for using asystem in accordance with the present disclosure to assess and/or treatone or more target nerves in the vicinity of an artery serving a targetorgan in a human subject. A catheter in accordance with the presentdisclosure may be advanced along an arterial pathway to the artery or abranch thereof serving the target organ. The catheter tip, equipped withone or more sensing elements, therapeutic elements, and/or substancedelivery elements, each in accordance with the present disclosure ispositioned within the artery such that the sensing elements are coupledto the local nerves surrounding the artery. In aspects, the catheter mayinclude a therapeutic element configured so as to deliver a therapeuticagent into or through the wall of the artery (e.g., so as to treat thetarget nerves), and a substance delivery element arranged such that abolus of a substance may be delivered into the lumen of the artery(e.g., so as to stress test a downstream organ, treat receptors in theorgan associated with the artery, etc.). Once placed within acorresponding artery, baseline readings of neural traffic are takenaround the wall of the artery. The nerve types, presence, and/orfunction are confirmed during baseline testing or during application ofa stress test in accordance with the present disclosure (e.g., such asvia delivery of a substance into the artery via the substance deliveryelement, etc.). Depending on the results of the analysis, an ablationprocedure, stimulation procedure, or selective neuro-remodelingprocedure may be completed with the catheter in accordance with thepresent disclosure, or the catheter may be moved to an alternative testsite, or removed from the subject. The sensing elements may beconfigured to monitor the associated neural traffic before, during,and/or after the procedure so as to assess when the procedure has beencompleted (e.g., when a target nerve has been functionally disabled,when a non-target nerve is starting to be affected by the therapy,etc.). Such a configuration may be advantageous for performing suchprocedures with a high degree of confidence related to the completionthereof, and to the minimizing of collateral damage associatedtherewith.

Example 13

The following, non-limiting example, is directed to treatment of cancer(e.g., pancreatic cancer), internal pain or neural mediated hyperplasiain organs (e.g., benign prostatic hyperplasia). Pancreatic carcinomacells (Mia PaCa2) were injected into the head of the pancreas of 10athymic nude mice (subjects). A bolus of ethanol (50-75 uL) wasadministered to the celiac ganglion and surrounding nerves of five ofthe mice (i.e., the EtOH ablation group). The remaining five subjectsconstitute the untreated control group.

The mice were tracked for 7 weeks post procedure. Tumor growth rates inall subjects were monitored via bioluminescent imaging with an in vivoimaging system, i.e., IVIS Spectrum (Xenogen), twice weekly during theexperiment. IVIS images from the median subject in each group at 3 weekspost procedure are shown in FIG. 11a . In FIG. 11a , the treatment armappears to show a substantially decreased tumor growth rate comparedwith the control arm (nearly a 100× difference in bioluminescencebetween the median responders). A logarithmic comparison between groupsof the tumor luminescence for each subject at 3 weeks is shown in FIG.11b . Overall, the mean tumor size in the experimental group is half ofthat of the control group (1-sided, alpha=0.05, n=5, p=0.11). Inaddition, the median tumor size at 3 weeks is less than 1% of thecontrol group median tumor size. As shown in FIG. 11b , a subset of theexperimental group did not respond to treatment, as complete neuralablation was likely not achieved in this sub group due to theexceptionally small and delicate nature of the murine target arteries.

The experiment was terminated at 7 weeks. FIG. 11c illustrates thatthere was no overall size difference between subjects in the groups at 7weeks. Thus, giving at least initial indication that the procedure issafe.

The metastases per group were assessed during necropsy. The results areshown in Tables 1 and 2 below. As shown, even with the non-respondersub-group, the incidence of metastases were considerably lower in theEtOH-treated group than in the untreated control group. Tables 1 and 2show that the overall rate of metastases to nearby sites including localinvasion, the stomach, and the liver were less in the EtOH-treated groupthan in the untreated control group. The two groups had the sameincidence of metastases traveling to the spleen. Note that the nervesrunning from the pancreas to the spleen were not treated during thisexperiment, but the procedure disclosed herein may be applied to suchnerves in large animals and humans so as to treat this pathwayseparately or in combination with the treatment of other anatomicalsites in the vicinity of the target organ. Results demonstrate thatoverall, there was less tumor mass in subjects with ablatedperi-pancreatic nerves than in subjects of the control group, fewermetastases in the ablated group, and similar overall body weightsbetween the ablated group and the control group.

TABLE 1 Occurrence of metastases by subject Mouse # Control Group EtOHAblation Group 1 Local invasion, spleen spleen 2 Local invasion Localinvasion, spleen 3 Local invasion, spleen none 4 Local invasion, spleen,liver Local invasion, spleen 5 Local invasion, spleen, liver, stomachspleen

TABLE 2 Occurrence of metastases by group Metastasis Site Control GroupEtOH ablation Group Local invasion 5/5 2/5 Spleen 4/5 4/5 Liver 2/5 0/5Stomach 1/5 0/5

Embodiments of the invention safely and effectively monitor and quantifysympathetic nerve activity from the porcine renal artery lumen, organparenchyma, and renal adventitia, with a clinically meaningful approach.Moreover, embodiments of the invention demonstrate that physiologicsignals can be monitored and used as feedback to indicate completion ofan ablation or neuromodulation procedure. Still further, embodiments ofthe invention show that tumor growth and metastases may be slowed byperi-pancreatic autonomic nerve ablation in an established and validatedmurine model of pancreatic cancer.

Embodiments of the invention locate (via sensing) and safely ablatepancreatic afferent/efferent neural control traffic to treat cancer, forexample, but not limited to, pancreatic cancer. In humans, thesensing-ablation techniques disclosed herein may enhance quality andquantity of life by at least the following mechanisms: relieve cancerpain safely, simply, and rapidly in patients suffering this fataldisease; improve blood glucose control resulting from tumor-induced betacell destruction; and improve survival through limiting inflammation andmetastases pathways.

Embodiments of the invention can be applied to any cancer, internalpain, or organ hyperplasia treatments. The methodologies and systemsdescribed herein may be applied to all solid cancers and in particular,perineural invading cancers. While the focus of illustrative embodimentsdescribed herein is not on ablating cancerous tissue, the methodologiesand systems described herein may be applied thereto.

Embodiments of the invention may be used to block or slow cancerprogression by: 1) reducing neurotransmitter release in the tumormicroenvironment that drives tumor growth (e.g., adrenaline); 2)disconnecting the microenvironment receptors from the CNS (to treat thecancer pain); and 3) blocking off the nerve pathways, which the cancercells migrate along during metastasis. Embodiments of the invention maybe used to treat any neurally mediated hyperplasia in organs, forexample, but not limited to, benign prostatic hyperplasia (BPH). Themethodologies and systems described herein may also be used for blockinginternal organ pain, for example, but not limited to, in treatingpancreatitis and general abdominal pain.

Notwithstanding the appended claims, the disclosure set forth herein isalso defined by the following clauses:

1. A system for treating a cancerous tumor, altering an organ function,and/or altering neural traffic in a microenvironment coupled to a targetorgan within a body, comprising:

a catheter or guidewire dimensioned for insertion into a lumen with awall, the lumen in fluid communication with the target organ and/or thetumor; and

the catheter or guidewire comprising a distal tip configured tointerface with the wall of the lumen, the distal tip configured todeliver energy and/or a substance to one or more nerves coupled to thetarget organ, and/or the wall of the lumen.

2. The system in accordance with clause 1, wherein the distal tipcomprises a balloon, a basket, a deployable helix, a deployablemicroneedle, or a combination thereof for interfacing with the wall.

3. The system in accordance with clause 1 or 2, wherein the energy isthermal energy, RF current, MW current, ultrasound, radiation,cryotherapy, or combinations thereof.

4. The system in accordance with any one of clauses 1-3, wherein thesubstance is a medicament, a denervating agent, an sympathetic nervespecific denervating agent, a parasympathetic nerve specific denervatingagent, a neuroblocking agent, a highly specific neuroblocking agent, ora combination thereof.

5. The system in accordance with clause 4, wherein the substance isethanol, phenol, botulinum toxin, a derivative, or a combinationthereof.

6. The system in accordance with any one of clauses 1-5, comprising oneor more sensing elements coupled with the distal tip, each sensingelement configured to interface with and/or monitor electrophysiologicalactivity from one or more of the nerves.

7. The system in accordance with any preceding clause, comprising asubstance eluting element coupled to the distal tip, configured todeliver a substance, a medicament, a denervating substance, orcombination thereof into the target organ, into a perivascular sitesurrounding the wall of the lumen, into the adventitia of the lumen,into a microenvironment of the tumor, into the lumen, or a combinationthereof.

8. The system in accordance with any preceding clause, wherein theenergy and/or substance is configured to interrupt, block, and/oraugment neural traffic along one or more nerves upon delivery from thedistal tip.

9. The system in accordance with any preceding clause, comprising aballoon coupled with the distal tip, the balloon coupled to a fluidsource so as to be expand-ably deployed during a procedure so as tointerface with the walls of lumen upon placement of the distal tiptherein.

10. The system in accordance with clause 9, wherein the ballooncomprises one or more energy delivery elements, and/or sensing elementsto interface with the wall of the lumen and/or the nerves.

11. The system in accordance with any one of clauses 6-10, wherein thesystem is configured to direct energy through the energy deliveryelements based upon the information collected by the sensing elements.

12. The system in accordance with any one of clauses 6-11, wherein thesensing elements are configured to monitor and/or determine the signalsrelating to regions of abnormal electrophysiological activity, determinethe direction of nerve traffic along nerves in the vicinity of thelumen, sympathetic neural activity in the vicinity of the lumen,determine the type of nerves situated near the sensing element,determine the effectiveness of the energy and/or substance delivery,determining the response of nerve traffic to a stress test performed onthe body or the organ, or combinations thereof.

13. The system in accordance with any preceding clause wherein thesystem is configured to direct the energy delivery into one or moreregions of the lumen wall, through the lumen wall, into the adventitia,into the target organ, adjacent to the lumen, into a microenvironment ofthe tumor, or combinations thereof.

14. The system in accordance with any one of clauses 6-13, comprising astress testing element, configured to apply a local and/or systemicstress to the body, one or more of the sensing elements configured tomonitor the response of the nerves to the stress.

15. The system in accordance with any one of clauses 1-14, wherein thedistal tip has a characteristic diameter of less than 1 mm, less than0.75 mm, less than 0.5 mm, or less than 0.3 mm so as to access the lumennear to or within a site within the target organ.

16. Use of a system in accordance with any one of clauses 6-15 todiagnose a disease state, determine a function of the wall, and/ordetermine a type of tissues adjacent to the lumen based upon the dataobtained by the one or more sensing elements.

17. Use of a system in accordance with any one of clauses 1-15 toreduce, and/or prevent communication of pain signals originating withina tumor microenvironment or associated organ from traveling along thenerve.

18. Use of a system in accordance with any one of clauses 1-15 to treatand/or slow the progression of a cancerous tumor.

19. Use of a system in accordance with any one of clauses 1-15 to treatcancer of the prostate, pancreas, breast, cervix, ovaries, bladder,bone, or combinations thereof.

20. Use of a system in accordance with any one of clauses 1-15 to slow,to reverse, and/or to prevent perineural invasion of a cancerous tumorinto a surrounding neural microenvironment.

21. Use of a system in accordance with any one of clauses 1-15 tointerrupt, decrease, and/or stop neural communication to/from acancerous tumor and/or the microenvironment surrounding the tumor to aremote site within a body.

22. Use of a system in accordance with any one of clauses 1-15 tomodulate, affect, slow, or halt tumorigenesis of a cancerous tissue sitewithin a body.

23. A method for treating a cancerous tumor, altering an organ function,and/or altering neural traffic in a microenvironment coupled to thetumor or a target organ within a body comprising:

accessing a wall of a lumen in the vicinity of the tumor or organ; and

delivering energy and/or a substance to at least a portion of the wallof the lumen, through at least a portion of the wall of the lumen, to anerve coupled with the tumor, and/or into the tissues surrounding thetumor or organ.

24. The method in accordance with clause 23 comprising, collectingphysiologic data from the tumor, from a nerve coupled to the tumor,and/or within the vicinity of the tumor and/or a perivasculature of thelumen.

25. The method in accordance with clause 24 comprising, directing theenergy and/or substance based upon the collected physiologic data.

26. The method in accordance with clause 25 comprising, collectingfurther physiologic data after the delivery of the energy and/or thesubstance to determine if the delivery affected the microenvironmentaround the tumor, the nerve coupled to the tumor, and/or theperivasculature of the lumen.

27. The method in accordance with any one of clauses 23-25, comprisingapplying a stress test to the subject during the collecting ofphysiologic data.

28. The method in accordance with clause 27, wherein the stress testcomprises a valsalva maneuver, a tilt table test, elevating one or morelegs, transient siting to standing exercises, execute a change inposture, move from a prone position to a sitting or standing position, abreath hold technique, or combinations thereof.

29. The method in accordance with clause 28, wherein the stress testcomprises injecting a vasodilator, a vasoconstrictor, a neuroblocker, aneurostimulant, a diuretic, insulin, glucose, beta-adrenergic receptorantagonist, angiotensin-11 converting enzyme inhibitor, calcium channelblocker, an HMG-CoA reductase inhibitor, digoxin, an anticoagulant, adiuretic, a beta blocker, an ACE inhibitor, a steroid, or combinationthereof to the organ and/or subject and monitoring the local responsethereto.

30. The method in accordance with clause 29, wherein the injection isdirected into the lumen, the adventitia surrounding the lumen, into thetumor, and/or into an organ coupled thereto.

31. The method in accordance with one of clauses 29-30, wherein the stepof injection is provided by a system in accordance with any one ofclauses 1-15.

32. The method in accordance with any one of clauses 23-29, wherein oneor more steps is performed with a system in accordance with any one ofclauses 1-15.

33. The method in accordance with any one of clauses 23-32, wherein thetarget organ is a bone.

34. The method in accordance with clause 33, wherein the energy and/orsubstance delivery is performed into a vessel, a periosteal space, aforamen, and/or a medullary cavity of the bone, or a combinationthereof.

35. The method in accordance with one of clauses 33 or 34, wherein thebone is a long bone and the lumen is a nutrient, epiphyseal, ormetaphyseal artery, vein or forma.

36. A method for treating a cancerous tumor within a body comprising,neuromodulating electrophysiological activity of one or more nervescoupled to the cancerous tumor and/or a microenvironment surrounding thetumor.

37. The method for treating a cancerous tumor in accordance with clause36, wherein the step of neuromodulating comprises stimulating, and/orablating the nerves.

38. The method for treating a cancerous tumor in accordance with one ofclauses 36 or 37, comprising monitoring the electrophysiologicalactivity before, during, and/or after the step of neuromodulating.

39. The method for treating a cancerous tumor in accordance with clause38, comprising determining the effectiveness of the step ofneuromodulating based upon the monitoring.

40. The method for treating a cancerous tumor in accordance with one ofclauses 38 or 39, comprising determining the type and/or location forthe step of neuromodulating based upon the monitoring.

41. The method for treating a cancerous tumor in accordance with any oneof clauses 36-40 wherein one or more steps are provided by a system inaccordance with any one of clauses 1-15.

42. Use of a method in accordance with any one of clauses 23-35 or anyone of clauses 36-41 to treat pancreatic cancer, prostate cancer, breastcancer, liver cancer, cervical cancer, ovarian cancer, bladder cancer,bone cancer, or combinations thereof.

43. A method for treating a cancerous tumor, altering an organ function,and/or altering neural traffic in a microenvironment coupled to thetumor or a target organ within a body comprising:

accessing a wall of a lumen in the vicinity of the tumor or organ;

monitoring baseline neural traffic in the vicinity of the lumen toidentify one or more target nerves; and

delivering energy and/or a substance to at least a portion of the wallof the lumen, through at least a portion of the wall of the lumen, tothe target nerves coupled with the tumor, and/or into the tissuessurrounding the tumor or organ.

44. The method in accordance with clause 43, wherein the step ofmonitoring comprises collecting physiologic data from the tumor, from anerve coupled to the tumor, and/or within the vicinity of the tumorand/or a perivasculature of the lumen.

45. The method in accordance with clause 43 or 44, comprising generatinga metric based upon the monitoring and/or physiologic data, the metricrelating to identification of the target nerve types, characterizationof the nerve traffic, determining the direction of target nerve traffic,locating nerve types in the vicinity of the lumen, or a combinationthereof.

46. The method in accordance with clause 44 or 45 comprising, directingthe energy and/or substance based upon the collected physiologic dataand/or the metric.

47. The method in accordance with any one of clauses 43-46 comprising,collecting further physiologic data and/or metrics after the delivery ofthe energy and/or the substance to determine if the delivery affectedthe neural traffic, the nerve function, the microenvironment around thetumor, the function of a target nerve coupled to the tumor, and/or theperivasculature of the lumen.

48. The method in accordance with any one of clauses 43-47, comprisingapplying a stress test to the subject during the collecting ofphysiologic data or neural monitoring.

49. The method in accordance with clause 48, wherein the stress testcomprises a Valsalva maneuver, a tilt table test, elevating one or morelegs, transient siting to standing exercises, execute a change inposture, move from a prone position to a sitting or standing position, abreath hold technique, or combinations thereof.

50. The method in accordance with clause 48, wherein the stress testcomprises injecting a vasodilator, a vasoconstrictor, a neuroblocker, aneurostimulant, a diuretic, insulin, glucose, beta-adrenergic receptorantagonist, angiotensin-11 converting enzyme inhibitor, calcium channelblocker, an HMG-CoA reductase inhibitor, digoxin, an anticoagulant, adiuretic, a beta blocker, an ACE inhibitor, a steroid, or combinationthereof to the organ and/or subject and monitoring the local responsethereto.

51. A system for treating a cancerous tumor, altering an organ function,and/or altering neural traffic in a microenvironment coupled to a targetorgan within a body, comprising:

a catheter or guidewire dimensioned for insertion into a lumen with awall, the lumen in fluid communication with the target organ and/or thetumor;

the catheter or guidewire comprising a distal tip configured tointerface with the wall of the lumen, the distal tip configured todeliver energy and/or a substance to one or more nerves coupled to thetarget organ, and/or the wall of the lumen; and

the distal tip comprising one or more sensing elements, the sensingelements configured to interface with the nerves and monitor nervetraffic therefrom.

52. The system in accordance with clause 51, wherein the system isconfigured such that the delivery of the energy and/or the substance isdirected based on the monitored nerve traffic.

53. The system in accordance with clause 51 or 52, comprising aprocessor, coupled with the sensing elements, the processor configuredto identify, locate, and/or assess the functionality of one or more ofthe nerves based upon the monitored nerve traffic.

54. The system in accordance with any one of clauses 52-53, wherein theprocessor is configured to modulate the effect of the delivery of theenergy and/or the substance on the nerves based on the monitored nervetraffic.

55. The system in accordance with any one of clauses 52-54, wherein theprocessor is configured to determine when to stop the delivery of theenergy and/or the substance based on the monitored nerve traffic.

56. The system in accordance with any one of clauses 51-55, wherein thedistal tip comprises a balloon, a basket, a deployable helix, adeployable microneedle, or a combination thereof for interfacing withthe wall.

57. The system in accordance with any one of clauses 51-56, wherein theenergy is thermal energy, RF current, MW current, ultrasound, radiation,cryotherapy, or combinations thereof.

58. The system in accordance with any one of clauses 51-56, wherein thesubstance is a medicament, a denervating agent, an sympathetic nervespecific denervating agent, a parasympathetic nerve specific denervatingagent, a neuroblocking agent, a highly specific neuroblocking agent, ora combination thereof.

59. The system in accordance with clause 58, wherein the substance isethanol, phenol, botulinum toxin, a derivative, or a combinationthereof.

60. The system in accordance with any one of clauses 51-59, wherein oneor more of the sensing elements is configured to interface with and/ormonitor electrophysiological activity from one or more of the nerves.

61. The system in accordance with any one of clauses 51-60, comprising asubstance eluting element coupled to the distal tip, configured todeliver a substance, a medicament, a denervating substance, orcombination thereof into the target organ, into a perivascular sitesurrounding the wall of the lumen, into the adventitia of the lumen,into a microenvironment of the tumor, into the lumen, or a combinationthereof.

62. The system in accordance with any one of clauses 51-61, wherein theenergy and/or substance is configured to interrupt, block, and/oraugment neural traffic along one or more nerves upon delivery from thedistal tip.

63. The system in accordance with any one of clauses 51-62, comprising aballoon coupled with the distal tip, the balloon coupled to a fluidsource so as to be expand-ably deployed during a procedure so as tointerface with the walls of lumen upon placement of the distal tiptherein.

64. The system in accordance with clause 63, wherein the ballooncomprises one or more energy delivery elements, and/or sensing elementsto interface with the wall of the lumen and/or the nerves.

65. The system in accordance with any one of clauses 51-64, wherein thesystem is configured to direct energy through the energy deliveryelements based upon the information collected by the sensing elements.

66. The system in accordance with any one of clauses 51-65, wherein thesensing elements are configured to monitor and/or determine the signalsrelating to regions of abnormal electrophysiological activity, determinethe direction of nerve traffic along nerves in the vicinity of thelumen, sympathetic neural activity in the vicinity of the lumen,determine the type of nerves situated near the sensing element,determine the effectiveness of the energy and/or substance delivery,determining the response of nerve traffic to a stress test performed onthe body or the organ, or combinations thereof.

67. The system in accordance with any one of clauses 51-66, wherein thesystem is configured to direct the energy delivery into one or moreregions of the lumen wall, through the lumen wall, into the adventitia,into the target organ, adjacent to the lumen, into a microenvironment ofthe tumor, or combinations thereof.

68. The system in accordance with any one of clauses 51-67, comprising astress testing element, configured to apply a local and/or systemicstress to the body, one or more of the sensing elements configured tomonitor the response of the nerves to the stress.

69. The system in accordance with any one of clauses 51-68, wherein thedistal tip has a characteristic diameter of less than 1 mm, less than0.75 mm, less than 0.5 mm, or less than 0.3 mm so as to access the lumennear to the target organ and/or near a site within the target organ.

It will be appreciated that additional advantages and modifications willreadily occur to those skilled in the art. Therefore, the disclosurespresented herein and broader aspects thereof, are not limited to thespecific details and representative embodiments shown and describedherein. Accordingly, many modifications, equivalents, and improvementsmay be included without departing from the spirit or scope of thegeneral inventive concept as defined by the appended claims and theirequivalents.

What is claimed is:
 1. A medical system, comprising: a microsurgicaltool defining a longitudinal axis, the microsurgical tool configured forpercutaneous introduction through a body lumen defined by a lumen walland having a distal tip segment positionable with respect to a targetneural structure, the distal tip segment comprising first, second andthird discrete zones longitudinally spaced with respect to thelongitudinal axis and each other; wherein the first zone comprises atleast a first component; wherein the second zone comprises at least asecond component; wherein the third zone is disposed between the firstand second zones, the third zone comprising at least a third component;wherein the first component and the second component each comprise asame one of: one or more physiological sensors; and one or morestimulatory elements; wherein the third component comprises the otherone of: one or more physiological sensors; and one or more stimulatoryelements; wherein the one or more physiological sensors are configuredto emit one or more signals representative of physiological data of thetarget neural structure; wherein the one or more stimulatory elementsare configured to apply stimulation to the target neural structure, theone or more stimulatory elements comprising at least one of one or moreenergy delivery elements and one or more substance delivery elements; acontroller to control operation of each of the first, second and thirdzones based on the physiological data obtained by the one or morephysiological sensors, the controller configured: to determine acondition of the target neural structure at least one of before, duringand subsequent to application of stimulation to the target neuralstructure by the one or more stimulatory elements; and to controloperation of the stimulatory element and coordinate positioning of thedistal tip segment relative to the target neural structure, based on thedetermined condition of the target neural structure.
 2. The medicalsystem of claim 1, wherein the one or more stimulatory elements comprisethe one or more energy delivery elements, the one or more energydelivery elements being configured to deliver energy adjacent the targetneural structure, the energy being at least one of thermal energy, radiofrequency current, microwave current, ultrasound, HIFU (high intensityfocused ultrasound), radiation, and cryotherapy.
 3. The medical systemof claim 1, wherein the one or more stimulatory elements comprise theone or more substance delivery elements, the one or more substancedelivery elements being configured to deliver a substance adjacent thetarget neural structure, the substance being at least one of amedicament, a denervating agent, a sympathetic nerve specificdenervating agent, a parasympathetic nerve specific denervating agent, aneuroblocking agent, and a highly specific neuroblocking agent.
 4. Themedical system of claim 3, wherein at least one of the one or moresubstance delivery elements comprises a microneedle.
 5. The medicalsystem of claim 1, wherein the first and second zones are each a sensingzone comprising the one or more physiological sensors, and the thirdzone is a stimulating zone comprising the one or more stimulatoryelements.
 6. The medical system of claim 5, wherein the third zone isconfigured to be biased toward the lumen wall such that the one or morestimulatory elements interface with the lumen wall.
 7. The medicalsystem of claim 6, further comprising a delivery sheath disposed aboutat least the distal tip segment of the microsurgical tool, the deliverysheath configured for longitudinal movement relative to themicrosurgical tool to expose the first, second and third zones.
 8. Themedical system of claim 1, wherein the distal tip segment comprises aballoon, a basket, a deployable helix, a deployable microneedle, or acombination thereof.
 9. The medical system of claim 1, furthercomprising: a stress testing element, the stress testing element beingconfigured to apply at least one of a local and a systemic stress to thelumen wall; and one or more sensing elements configured to monitor aresponse of the target neural structure to the applied stress.
 10. Themedical system of claim 1, wherein the controller is configured toselectively adjust positioning of at least the distal tip segment of themicrosurgical tool relative to a tumor based on the determined conditionof the target neural structure.
 11. A medical system, comprising: amicrosurgical tool defining a longitudinal axis, the microsurgical toolconfigured for percutaneous introduction through a body lumen defined bya lumen wall and having a distal tip segment positionable with respectto a target neural structure, the distal tip segment comprising at leasttwo zones, a first one of the at least two zones comprising one or morephysiological sensors configured to emit a signal representative ofphysiological data of the target neural structure and a second of the atleast two zones comprising one or more stimulatory elements configuredto apply stimulation to the target neural structure, the first zone andthe second zone longitudinally spaced with respect to each other alongthe distal tip segment relative to the longitudinal axis, the one ormore stimulatory elements of the second zone comprising at least one ofan energy delivery element and a substance delivery element; and acontroller to control operation of each of the at least two zones basedon the physiological data obtained by the one or more physiologicalsensors, the controller configured: to determine a condition of theneural structure at least one of before, during and subsequent toapplication of stimulation to the neural structure by the one or morestimulatory elements; and to control operation of the one or morestimulatory elements based on the determined condition of the neuralstructure; wherein the distal tip segment comprises one or more strainmeasuring elements configured to measure a diameter of the body lumen.12. A medical system, comprising: a microsurgical tool defining alongitudinal axis, the microsurgical tool configured for percutaneousintroduction through a body lumen defined by a lumen wall and having adistal tip segment positionable with respect to a target neuralstructure, the distal tip segment comprising: first and second zoneslongitudinally spaced with respect to each other along the distal tipsegment relative to the longitudinal axis, each of the first and secondzones comprising one or more physiological sensors configured to emitone or more signals representative of physiological data of the targetneural structure; and a third zone disposed between the first and secondzones, the third zone comprising one or more electrodes configured toapply stimulation to the target neural structure, the third zone beingdeployable such that the one or more electrodes interface with the lumenwall; a controller to control operation of at least the third zone basedon the physiological data obtained by the one or more physiologicalsensors of the first and second zones, the controller configured: todetermine a condition of the target neural structure at least one ofbefore, during and subsequent to application of stimulation to thetarget neural structure by the one or more electrodes of the third zone;and to continually control operation of the one or more electrodes ofthe third zone based on the determined condition of the target neuralstructure; and an array of microcircuits arranged along a predeterminedlength of the distal tip segment, the array of microcircuits couplingthe one or more physiological sensors and the one or more electrodeswith the controller, the array of microcircuits providing signalconditioning of the one or more signals representative of thephysiological data of the target neural structure emitted by the one ormore physiological sensors; and one or more strengthening memberscoupled with the array of microcircuits.
 13. The medical system of claim12, wherein the third zone is configured to be biased toward the lumenwall such that the one or more electrodes interface with the lumen wall.14. The medical system of claim 12, wherein the third zone isincorporated within a deployable segment of the distal tip segment, thedeployable segment comprising one of a balloon, a basket, a helix, amicroneedle, or a combination thereof.
 15. The medical system of claim14, further comprising a delivery sheath disposed about at least thedeployable segment of the distal tip segment, the delivery sheathconfigured for longitudinal movement relative to the distal tip segmentto expose the deployable segment.
 16. The medical system of claim 12,wherein the distal tip segment comprises one or more strain measuringelements configured to measure a diameter of the body lumen.
 17. Themedical system of claim 12, wherein the distal tip segment furthercomprises one or more substance delivery elements, the one or moresubstance delivery elements configured to deliver a substance adjacentthe target neural structure, the substance being at least one of amedicament, a denervating agent, a sympathetic nerve specificdenervating agent, a parasympathetic nerve specific denervating agent, aneuroblocking agent, and a highly specific neuroblocking agent.
 18. Themedical system of claim 12, wherein individual microcircuits in thearray of microcircuits are arranged in a single file linear patternalong the predetermined length of the distal tip segment.
 19. Themedical system of claim 12, wherein the one or more strengtheningmembers allow at least one of compression, tension and torque transferalong the predetermined length of the distal tip segment.
 20. Themedical system of claim 12, wherein the array of microcircuits arecoupled to the one or more physiological sensors and the one or moresensors utilizing an ultra-high density interconnect technology.